Compositions, formulations and methods for treating ocular diseases

ABSTRACT

Disclosed herein are compounds effective for activation of Tie-2 and inhibition of HPTP-beta. The compounds can provide effective therapy for conditions associated with angiogenesis, for example, ocular conditions. Formulations for increased solubility are disclosed. Combination therapy with antibodies and PK/PD data are also disclosed.

CROSS REFERENCE

This Application claims the benefit of U.S. Provisional Application No.61/792,868, filed Mar. 15, 2013, U.S. Provisional Application No.61/792,679, filed Mar. 15, 2013, U.S. Provisional Application No.61/882,056, filed Sep, 25, 2013, U.S. Provisional Application No.61/882,048, filed Sep, 25, 2013 and U.S. Provisional Application No.61/934,570, filed Jan. 31, 2014, each of which is incorporated herein byreference in its entirety.

FIELD

Disclosed herein are compositions, formulations, and methods fortreating ocular diseases, inter alia, diabetic macular edema,age-related macular degeneration (wet form), choroidalneovascularization, diabetic retinopathy, retinal vein occlusion(central or branch), ocular trauma, surgery induced edema, surgeryinduced neovascularization, cystoid macular edema, ocular ischemia,uveitis, and the like. These diseases or conditions are characterized bychanges in the ocular vasculature whether progressive ornon-progressive, whether a result of an acute disease or condition, or achronic disease or condition.

INCORPORATION BY REFERENCE

Each patent, publication, and non-patent literature cited in theapplication is hereby incorporated by reference in its entirety as ifeach was incorporated by reference individually.

BACKGROUND

The eye comprises several structurally and functionally distinctvascular beds, which supply ocular components critical to themaintenance of vision. These include the retinal and choroidalvasculatures, which supply the inner and outer portions of the retina,respectively, and the limbal vasculature located at the periphery of thecornea. Injuries and diseases that impair the normal structure orfunction of these vascular beds are among the leading causes of visualimpairment and blindness. For example, diabetic retinopathy is the mostcommon disease affecting the retinal vasculature, and is the leadingcause of vision loss among the working age population in the UnitedStates. Vascularization of the cornea secondary to injury or disease isyet another category of ocular vascular disease that can lead to severeimpairment of vision.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the results of two phase three studies to determine theeffect of intravitreal injections of ranibizumab in patients withdiabetic macular edema.

FIG. 2 depicts the results of a study wherein 4 patients received 5 mgof the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily for 28 days and subsequently weretreated in one or both eyes (7 eyes total) with either ranibizumab (0.3or 0.5 mg) or aflibercept (2 mg) by intravitreal injection at thediscretion of the study investigator.

FIG. 3 depicts the results of phase three studies to determine theeffect of intravitreal injections of ranibizumab in patients withdiabetic macular edema.

FIG. 4 depicts the increased visual acuity of a study wherein 4 patientsreceived 5 mg of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily for 28 days and subsequently weretreated with either ranibizumab (0.3 or 0.5 mg) or aflibercept (2 mg) byintravitreal injection.

FIG. 5 graphs changes in central foveal thickness over time in an eyetreated with a drug/antibody combination.

FIG. 6 graphs changes in central foveal thickness over time in an eyetreated with a drug/antibody combination.

FIG. 7 is a graphic representation of in vivo experiments performed in 6week old C57BL/6 mice.

FIG. 8A illustrates the extent of choroidal neovascularization evidentin a control sample stained with FITC-labeled Griffonia simplicifolia(GSA) of the experiment of FIG. 7.

FIG. 8B represents the extent of neovascularization in the choroidaltissue of animals treated with aflibercept, stained with FITC-labeledGriffonia simplicifolia (GSA).

FIG. 8C represents the extent of neovascularization in tissue treatedwith a Tie-2 signaling enhancer, tissue stained with FITC-labeledGriffonia simplicifolia (GSA).

FIG. 8D represents the extent of neovascularization present in tissuereceiving a combined therapy of aflibercept and the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid, stained with FITC-labeled Griffonia simplicifolia (GSA).

FIG. 9 shows the plasma concentration of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid, pre-dose(O), 15 minutes, 1 hour, 2 hours, 3 hours and 4 hoursafter administration after the first dose on day 14.

SUMMARY OF THE INVENTION

In some embodiments, the invention provides a method of treating acondition in a subject in need thereof, the method comprisingadministering to the subject a therapeutically-effective amount of acompound that activates Tie-2, or a pharmaceutically-acceptable saltthereof, and an agent that increases solubility of the compound thatactivates Tie-2, or the pharmaceutically-acceptable salt thereof ascompared to solubility in absence of the agent.

In some embodiments, the invention provides a method of treating acondition in a subject in need thereof, the method comprisingadministering to the subject a therapeutically-effective amount of acompound that activates Tie-2, or a pharmaceutically-acceptable saltthereof, wherein the administration provides a plasma concentration inthe subject of the compound that activates Tie-2 or thepharmaceutically-acceptable salt thereof of about 25 ng/mL to about 500ng/mL.

In some embodiments, the invention provides a pharmaceutical compositioncomprising: a) a compound that activates Tie-2, or apharmaceutically-acceptable salt thereof; and b) an agent that improvesthe aqueous solubility of the compound that activates Tie-2, or thepharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a pharmaceutical compositioncomprising: a) a Tie-2 activator or a pharmaceutically-acceptable saltthereof; and b) an antibody.

In some embodiments, the invention provides a kit comprising: a) a Tie-2activator or a pharmaceutically-acceptable salt thereof; b) an antibody;and c) written instructions on use of the kit in treatment of acondition.

In some embodiments, the invention provides a method of treating acondition, the method comprising administering to a subject in needthereof: a) a therapeutically-effective amount of a Tie-2 activator or apharmaceutically-acceptable salt thereof; and b) atherapeutically-effective amount of an antibody.

In some embodiments, the invention provides a complex comprising: a) aTie-2 activator, or a pharmaceutically-acceptable salt thereof; and b) amolecule comprising a channel, wherein the compound that activatesTie-2, or the pharmaceutically-acceptable salt thereof is held in thechannel of the molecule by non-covalent interactions.

In some embodiments, the invention provides a method of treating acondition, the method comprising administering to a subject in needthereof a therapeutically-effective amount of complex comprising: a) aTie-2 activator, or a pharmaceutically-acceptable salt thereof; and b) amolecule comprising a channel, wherein the compound that activatesTie-2, or the pharmaceutically-acceptable salt thereof is held in thechannel of the molecule by non-covalent interactions.

DETAILED DESCRIPTION

Provided herein are compounds and methods of treating ocular disordersthat are characterized by vascular instability, vascular leakage, andneovascularization. HPTP-β is a member of the receptor-like family ofthe protein tyrosine phosphatases (PTPases). HPTP-β is a transmembraneprotein found primarily in endothelial cells that displays structuraland functional similarity to cell adhesion molecules (CAMs). HPTP-β isunique among receptor-like PTPases in that it contains a singlecatalytic domain One of the main functions of HPTP-β is to regulateTie-2 negatively.

Tie-2 is a receptor tyrosine kinase found almost exclusively inendothelial cells. The principle regulators of Tie-2 phosphorylation areAngiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2). Upon Angiopoietin-1binding to Tie-2, the level of Tie-2 receptor phosphorylation increases.The duration of Tie-2 receptor phosphorylation is regulated by HPTP-β,which cleaves off the phosphate. Tie-2 receptor phosphorylation helpsmaintain endothelial cell proximity; therefore, the duration of Tie-2receptor phosphorylation is an important determinant of endothelial cellproximity For example, when severe inflammation occurs, the capillaryendothelial cells separate, allowing proteins, to enter the interstitialspace. Separation of the capillary endothelial cells, and subsequentleak of proteins in the interstitial space, is known as vascular leakand can lead to dangerous hypotension (low blood pressure), edema,hemoconcentration, and hypoalbuminemia. Inhibition of HPTP-β leads toincreased levels and Tie-2 receptor phosphorylation, a process that canmaintain or restore capillary endothelial cell proximity

The present disclosure relates to compositions and methods for treatingconditions, such as ocular diseases, for example, those whereinneovasculatization and vascular leakage are present. These diseases aresometimes characterized as diseases wherein there is an elevatedangiogenic response in the vessels associated with the eye. The presentdisclosure provides a Human Protein Tyrosine Phosphatase-beta (HPTP-β)inhibitor that provides vascular stabilization.

Human Protein Tyrosine Phosphatase-beta (HPTP-β) Inhibitors.

Compounds disclosed herein can be effective as Tie-2 activators. Thecompounds can effect that activity, for example, by binding orinhibiting HPTP-β Such compounds can bind, for example, by mimicking thebinding mechanism of a native substrate, such as a phosphorylatedcompound. A compound can be a phosphate mimetic or bioisostere, forexample, a sulfamic acid. The compound could also be derived from anamino acid building block or comprise an amino acid backbone forefficiency and economy of synthesis.

In some embodiments, a compound of the invention is a compound offormula:

wherein: Aryl¹ is an aryl group which is substituted or unsubstituted;Aryl² is an aryl group which is substituted or unsubstituted; X isalkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, anamide linkage, an ester linkage, a thioether linkage, a carbamatelinkage, a carbonate linkage, a urethane linkage, a sulfone linkage, anyof which is substituted or unsubstituted, or a chemical bond; and Y isH, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g),any of which is substituted or unsubstituted, or

wherein L² is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a urethanelinkage, or a sulfonamide linkage, or a chemical bond, or together withany of R^(a), R^(b), R^(c), and R^(d) forms a ring that is substitutedor unsubstituted. R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L²,R^(b), R^(c), and R^(d) forms a ring that is substituted orunsubstituted. R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L²,R^(a), R^(c), and R^(d) forms a ring that is substituted orunsubstituted. R^(c) is H or alkyl which is substituted orunsubstituted, or together with any of L², R^(a), R^(b), and R^(d) formsa ring that is substituted or unsubstituted. R^(d) is H or alkyl whichis substituted or unsubstituted, or together with any of L², R^(a),R^(b), and R^(c) forms a ring that is substituted or unsubstituted, andR^(g) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or a pharmaceutically-acceptable salt,tautomer, or zwitterion thereof.

In some embodiments, aryl¹ is substituted or unsubstituted phenyl, aryl²is substituted or unsubstituted heteroaryl, and X is alkylene. In someembodiments, aryl¹ is substituted phenyl, aryl² is substitutedheteroaryl, and X is methylene.

In some embodiments, a compound is of the fomula:

wherein wherein aryl¹ is para-substituted phenyl, aryl² is substitutedheteroaryl, X is methylene. L² is alkylene, alkenylene, or alkynylene,any of which is substituted or unsubstituted, or together with thenitrogen atom to which L is bound forms an amide linkage, a carbamatelinkage, a urethane linkage, or a sulfonamide linkage, or a chemicalbond. R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted. R^(b) is H, alkyl, alkenyl,alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,or heteroarylalkyl, any of which is substituted or unsubstituted. R^(c)is H or alkyl which is substituted or unsubstituted, and R^(d) is H oralkyl which is substituted or unsubstituted.

In some embodiments, aryl¹ is para-substituted phenyl, aryl² is asubstituted thiazole moiety. X is methylene, L² together with thenitrogen atom to which L is bound forms a carbamate linkage, R^(a) isalkyl, which is substituted or unsubstituted, R^(b)is arylalkyl, whichis substituted or unsubstituted, R^(c) is H, and R^(d) is H.

In some embodiments, Aryl² is:

wherein R^(c) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a urethane group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, and R^(f) is H, OH, F, Cl, Br, I, CN,alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylicacid group, a carboxaldehyde group, an ester group, an amine group, anamide group, a carbonate group, a carbamate group, a urethane group, athioether group, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted.

In some embodiments, R^(e) is H, OH, F, Cl, Br, I, alkyl, an alkoxygroup, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted, and R^(f)is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted. In some embodiments, R^(e) is H,OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substitutedor unsubstituted and R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl,any of which is substituted or unsubstituted. In some embodiments, aryl¹is 4-phenylsulfamic acid, R^(a) is alkyl, which is substituted orunsubstituted, R^(b) is arylalkyl, which is substituted orunsubstituted, R^(e) is H; and R^(f) is heteroaryl. In some embodiments,aryl¹ is 4-phenylsulfamic acid, R^(a) is alkyl, which is substituted orunsubstituted, R^(b) is arylalkyl, which is substituted orunsubstituted, R^(e) is H; and R^(f) is alkyl

In some embodiments, Aryl² is:

wherein R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a urethane group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, R^(f) is H, OH, F, Cl, Br, I, CN, alkyl,alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a urethane group, athioether group, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted. In some embodiments, R^(e) is H,OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted and R^(f) is H, OH, F, Cl, Br, I, alkyl, analkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted. In some embodiments, R^(e) is H, OH, F, Cl, Br, I, alkyl,or an alkoxy group, any of which is substituted or unsubstituted andR^(f) is alkyl, aryl, heterocyclyl, or heteroaryl, any of which issubstituted or unsubstituted. In some embodiments, aryl¹ is4-phenylsulfamic acid, R^(a) is alkyl, which is substituted orunsubstituted, R^(b) is arylalkyl, which is substituted orunsubstituted, R^(e) is H; and R^(f) is heteroaryl.

In some embodiments, a substituted phenyl group is:

wherein: each of R^(ph1), RP^(h2), R^(ph3), R^(ph4), and R^(ph5) isindependently H, OH, F, Cl, Br, I, CN, sulamic acid, tosylate, mesylate,triflate, besylate, alkyl, alkenyl, alkynyl, an alkoxy group, asulfhydryl group, a nitro group, a nitroso group, an azido group, asulfoxide group, a sulfone group, a sulfonamide group, an ether group, acarboxylic acid group, a carboxaldehyde group, an ester group, an aminegroup, an amide group, a carbonate group, a carbamate group, a urethanegroup, a thioether group, a thioester group, a thioacid group, aryl,arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl

Optional Substituents for Chemical Groups.

Non-limiting examples of optional substituents include hydroxyl groups,sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups,cyano groups, azido groups, sulfoxide groups, sulfone groups,sulfonamide groups, carboxyl groups, carboxaldehyde groups, iminegroups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenylgroups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups,aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups,acyl groups, acyloxy groups, carbamate groups, amide groups, urethanegroups, and ester groups.

The following are non-limiting examples of units which can substitutefor hydrogen atoms:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂), ethynyl (C₂),        n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), 3-propenyl        (C₃), 1-propenyl (also 2-methylethenyl) (C₃), isopropenyl (also        2-methylethen-2-yl) (C₃), prop-2-ynyl (also propargyl) (C₃),        propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),        tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl        (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings;    -   vi) —(CR^(102a)R^(102b))_(a)OR¹⁰¹; for example, —OH, —CH₂OH,        —OCH₃, —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(102a)R^(102b))_(a)C(O)R¹⁰¹; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(102a)R^(102b))_(a)C(O)OR¹⁰¹ ; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹ )₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;

xi) halogen; —F, —Cl, —Br, and —I;

-   -   xii) —(CR^(102a)R^(102b))_(a)CN;    -   xiii) —(CR^(102a)R^(102b))_(a)NO₂;    -   xiv) —CH_(j)X_(k); wherein X is halogen, the index j is an        integer from 0 to 2, j+k=3; for example, —CH₂F, —CHF₂, —CF₃,        —CCl₃, or —CBr₃;    -   xv) —(CR^(102a)R^(102b))_(a)SR¹⁰¹; SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(102a)R^(102b))_(a)SO₂R¹⁰¹; for example, —SO₂H,        —CH₂SO₂H, —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(102a)R^(102b))_(a)SO₃R¹⁰¹; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R^(ail) is independently hydrogen, substituted or        unsubstituted C₁-C₆ linear, branched, or cyclic alkyl, phenyl,        benzyl, heterocyclic, or heteroaryl; or two R¹⁰¹ units can be        taken together to form a ring comprising 3-7 atoms; R^(102s) and        R^(102b) are each independently hydrogen or C₁-C₄ linear or        branched alkyl; the index “a” is from 0 to 4.

Non-limiting examples of alkyl and alkylene groups include straight,branched, and cyclic alkyl and alkylene groups. An alkyl group can be,for example, a C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃,C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, C₂₄, C₂₅, C₂₆, C₂₇,C₂₈, C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄, C₃₅, C₃₆, C₃₇, C₃₈, C₃₉, C₄₀, C₄₁,C₄₂, C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈, C₄₉, or C₅₀ group that is substitutedor unsubstituted.

Non-limiting examples of straight alkyl groups include methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

Branched alkyl groups include any straight alkyl group substituted withany number of alkyl groups. Non-limiting examples of branched alkylgroups include isopropyl, isobutyl, sec-butyl, and t-butyl.

Non-limiting examples of cyclic alkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctylgroups. Cyclic alkyl groups also include fused-, bridged-, andspiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclicalkyl group can be substituted with any number of straight, branched, orcyclic alkyl groups.

Non-limiting examples of alkenyl and alkenylene groups include straight,branched, and cyclic alkenyl groups. The olefin or olefins of an alkenylgroup can be, for example, E, Z, cis, trans, terminal, or exo-methylene.An alkenyl or alkenylene group can be, for example, a C₂, C₃, C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀,C₂₁, C₂₂, C₂₃, C₂₄, C₂₅, C₂₆, C₂₇, C₂₈, C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄,C₃₅, C₃₆, C₃₇, C₃₈, C₃₉, C₄₀, C₄₁, C₄₂, C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈,C₄₉, or C₅₀ group that is substituted or unsubstituted.

Non-limiting examples of alkynyl or alkynylene groups include straight,branched, and cyclic alkynyl groups. The triple bond of an alkylnyl oralkynylene group can be internal or terminal An alkylnyl or alkynylenegroup can be, for example, a C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, C₂₄, C₂₅,C₂₆, C₂₇, C₂₈, C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄, C₃₅, C₃₆, C₃₇, C₃₈, C₃₉,C₄₀, C₄₁, C₄₂, C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈, C₄₉, or C₅₀ group that issubstituted or unsubstituted.

Non-limiting examples of substituted and unsubstituted acyclichydrocarbyl include:

-   -   1) linear or branched alkyl, non-limiting examples of which        include, methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl        (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), tert-butyl        (C₄), and the like; substituted linear or branched alkyl,        non-limiting examples of which includes, hydroxymethyl (C₁),        chloromethyl (C₁), trifluoromethyl (C₁), aminomethyl (C₁),        1-chloroethyl (C₂), 2-hydroxyethyl (C₂), 1,2-difluoroethyl (C₂),        and 3-carboxypropyl (C₃).    -   2) linear or branched alkenyl, non-limiting examples of which        include, ethenyl (C₂), 3-propenyl (C₃), 1-propenyl (also        2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl)        (C₃), buten-4-yl (C₄), and the like; substituted linear or        branched alkenyl, non-limiting examples of which include,        2-chloroethenyl (also 2-chlorovinyl) (C₂), 4-hydroxybuten-1-yl        (C₄), 7-hydroxy-7-methyloct-4-en-2-yl (C₉), and        7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉).    -   3) linear or branched alkynyl, non-limiting examples of which        include, ethynyl (C₂), prop-2-ynyl (also propargyl) (C₃),        propyn-1-yl (C₃), and 2-methyl-hex-4-yn-1-yl (C₇); substituted        linear or branched alkynyl, non-limiting examples of which        include, 5-hydroxy-5-methylhex-3- ynyl (C₇),        6-hydroxy-6-methylhept-3-yn-2-yl (C₈), and        5-hydroxy-5-ethylhept-3- ynyl (C₉).

Non-limiting examples of substituted and unsubstituted cyclichydrocarbyl include: rings comprising from 3 to 20 carbon atoms, whereinthe atoms which comprise said rings are limited to carbon atoms, andfurther each ring can be independently substituted with one or moremoieties capable of replacing one or more hydrogen atoms. The followingare non-limiting examples of substituted and unsubstituted carbocyclicrings:

-   i) carbocyclic rings having a single substituted or unsubstituted    hydrocarbon ring, non-limiting examples of which include,    cyclopropyl (C₃), 2-methyl-cyclopropyl (C₃), cyclopropenyl (C₃),    cyclobutyl (C₄), 2,3-dihydroxycyclobutyl (C₄), cyclobutenyl (C₄),    cyclopentyl (C₅), cyclopentenyl (C₅), cyclopentadienyl (C₅),    cyclohexyl (C₆), cyclohexenyl (C₆), cycloheptyl (C₇), cyclooctanyl    (C₈), 2,5-dimethylcyclopentyl (C₅), 3,5-dichlorocyclohexyl (C₆),    4-hydroxycyclohexyl (C₆), and 3,3,5-trimethylcyclohex-1 (C₆).-   ii) carbocyclic rings having two or more substituted or    unsubstituted fused hydrocarbon rings, non-limiting examples of    which include, octahydropentalenyl (C₈), octahydro-1H-indenyl (C₉),    3a,4,5,6,7,7a-hexahydro-3H-inclen-4-yl (C₉), decahydroazulenyl    (C₁₀).-   iii) carbocyclic rings which are substituted or unsubstituted    bicyclic hydrocarbon rings, non-limiting examples of which include,    bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl,    bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl,    bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

Also included are C₁-C₆ tethered cyclic hydrocarbyl units (whethercarbocyclic units, C₆ or C₁₀ aryl units, heterocyclic units, orheteroaryl units) can be connected to another moiety, unit, or core ofthe molecule by way of a C₁-C₆ alkylene unit. Non-limiting examples oftethered cyclic hydrocarbyl units include benzyl C₁-(C₆) having theformula:

wherein R^(a) is optionally one or more independently chosensubstitutions for hydrogen. Further examples include other aryl units,inter alia, (2-hydroxyphenyl)hexyl C₆-(C₆); naphthalen-2-ylmethylC₁-(C₁₀), 4-fluorobenzyl C₁-(C₆), 2(3-hydroxyphenyl)ethyl C₂-(C₆), aswell as substituted and unsubstituted C₃-C₁₀ alkylenecarbocyclic units,for example, cyclopropylmethyl C₁-(C₃), cyclopentylethyl C₂-(C₅),cyclohexylmethyl C₁-(C₆);. Included within this category are substitutedand unsubstituted C₁-C₁₀ alkylene-heteroaryl units, for example a2-picolyl C₁-(C₆) unit having the formula:

wherein R^(a) is the same as defined above. In addition, C₁-C₁₂ tetheredcyclic hydrocarbyl units include C₁-C₁₀ alkyleneheterocyclic units andalkylene-heteroaryl units, non-limiting examples of which include,aziridinylmethyl C₁-(C₂) and oxazol-2-ylmethyl C₁-(C₃).

A halo group can be any halogen atom, for example, fluorine, chlorine,bromine, or iodine.

A halo-alkyl group can be any alkyl group substituted with any number ofhalogen atoms, for example, fluorine, chlorine, bromine, and iodineatoms. A halo-alkenyl group can be any alkenyl group substituted withany number of halogen atoms. A halo-alkynyl group can be any alkynylgroup substituted with any number of halogen atoms.

An alkoxy group can be, for example, an oxygen atom substituted with anyalkyl, alkenyl, or alkynyl group. An ether or an ether group comprisesan alkoxy group. Non-limiting examples of alkoxy groups include methoxy,ethoxy, propoxy, isopropoxy, and isobutoxy.

An aryl group can be heterocyclic or non-heterocyclic. An aryl group canbe monocyclic or polycyclic. An aryl group can be substituted with anynumber of substituents described herein, for example, hydrocarbylgroups, alkyl groups, alkoxy groups, and halogen atoms. Non-limitingexamples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl,pyridyl, imidazolyl, thiophenyl, and furyl.

Non-limiting examples of aryl groups can include: i) C₆ or C₁₀substituted or unsubstituted aryl rings; phenyl and naphthyl ringswhether substituted or unsubstituted, non-limiting examples of whichinclude, phenyl (C₆), naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀),4-fluorophenyl (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆),2-amino-4-fluorophenyl (C₆), 2-(N,N-diethylamino)phenyl (C₆),2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆), 3-methoxyphenyl (C₆),8-hydroxynaphthylen-2-yl (C₁₀), 4,5-dimethoxynaphthylen-1-yl (C₁₀), and6-cyano-naphthylen-1-yl (C₁₀); and ii) C₆ or C₁₀ aryl rings fused with 1or 2 saturated rings to afford C₈-C₂₀ ring systems, non-limitingexamples of which include, bicyclol4.2.0locta-1,3,5-trienyl (C₈), andindanyl (C₉).

An aryloxy group can be, for example, an oxygen atom substituted withany aryl group, such as phenoxy.

An aralkyl group can be, for example, any alkyl group substituted withany aryl group, such as benzyl.

An arylalkoxy group can be, for example, an oxygen atom substituted withany aralkyl group, such as benzyloxy.

A heterocycle can be any ring containing a ring atom that is not carbon,for example, N, O, S, P, Si, B, or any other heteroatom. A heterocyclecan be substituted with any number of substituents, for example, alkylgroups and halogen atoms. A heterocycle can be aromatic (heteroaryl) ornon-aromatic. Non-limiting examples of heterocycles include pyrrole,pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine,imidazole, thiophene, furan, tetrahydrofuran, pyran, andtetrahydropyran.

Non-limiting examples of heterocycles include: heterocyclic units havinga single ring containing one or more heteroatoms, non-limiting examplesof which include, diazirinyl (C₁), aziridinyl (C₂), urazolyl (C₂),azetidinyl (C₃), pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl(C₃), isoxazolinyl (C₃), thiazolidinyl (C₃), isothiazolinyl (C₃),oxathiazolidinonyl (C₃), oxazolidinonyl (C₃), hydantoinyl (C₃),tetrahydrofuranyl (C₄), pyrrolidinyl (C₄), morpholinyl (C₄), piperazinyl(C₄), piperidinyl (C₄), dihydropyranyl (C₅), tetrahydropyranyl (C₅),piperidin-2-onyl (valerolactam) (C₅), 2,3,4,5-tetrahydro-1H-azepinyl(C₆), 2,3-dihydro-1H-indole (C₈), and 1,2,3,4-tetrahydroquinoline (C₉);and ii) heterocyclic units having 2 or more rings one of which is aheterocyclic ring, non-limiting examples of which includehexahydro-1H-pyrrolizinyl (C₇),3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl (C₇),3a,4,5,6,7,7a-hexahydro-1H-indolyl (C₈), 1,2,3,4-tetrahydroquinolinyl(C₉), and decahydro-1H-cycloocta[b]pyrrolyl (C₁₀).

Non-limiting examples of heteroaryl include: i) heteroaryl ringscontaining a single ring, non-limiting examples of which include,1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂),triazinyl (C₃), thiazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl (C₃),isoxazolyl (C₃), isothiazolyl (C₃), furanyl (C₄), thiophenyl (C₄),pyrimidinyl (C₄), 2-phenylpyrimidinyl (C₄), pyridinyl (C₅),3-methylpyridinyl (C₅), and 4-dimethylaminopyridinyl (C₅); and ii)heteroaryl rings containing 2 or more fused rings one of which is aheteroaryl ring, non-limiting examples of which include: 7H-purinyl(C₅), 9H-purinyl (C₅), 6-amino-9H-purinyl (C₅),5H-pyrrolo[3,2-d]pyrimidinyl (C₆), 7H-pyrrolo[2,3-d]pyrimidinyl (C₆),pyrido[2,3-d]pyrimidinyl (C₇), 2-phenylbenzo[d]thiazolyl (C₇),1H-indolyl (C₈), 4,5,6,7-tetrahydro-1-H-indolyl (C₈), quinoxalinyl (C₈),5-methylquinoxalinyl (C₈), quinazolinyl (C₈), quinolinyl (C₉),8-hydroxy-quinolinyl (C₉), and isoquinolinyl (C₉).

Non-limiting examples of heteroaryl include 1,2,3,4-tetrahydroquinolinehaving the formula:

6,7-Dihydro-5H-cyclopentapyrimidine having the formula

and

1,2,3,4-tetrahydro-[1,8]naphthpyridine having the formula

An acyl group can be, for example, a carbonyl group substituted withhydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl,arylalkoxy, or a heterocycle. Non-limiting examples of acyl includeacetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl,and ethoxycarbonyl.

An acyloxy group can be an oxygen atom substituted with an acyl group.An ester or an ester group comprises an acyloxy group. A non-limitingexample of an acyloxy group, or an ester group, is acetate.

A carbamate group can be an oxygen atom substituted with a carbamoylgroup, wherein the nitrogen atom of the carbamoyl group isunsubstituted, monosubstituted, or disubstituted with one or more ofhydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogenatom is disubstituted, the two substituents together with the nitrogenatom can form a heterocycle.

Compounds of the Invention.

In some embodiments, a compound of the disclosure has Formula (I):

wherein the carbon atom having the amino unit has the stereochemistryindicated in the following formula:

The units which comprise R and Z can comprise units having anyconfiguration, and, as such, a compound of the disclosure can be asingle enantiomer, a diastereomer, or pairs or combinations thereof. Inaddition, the compounds can be isolated as salts or hydrates. In thecase of salts, the compounds can comprise more than one cation or anion.In the case of hydrates, any number of water molecules, or fractionalpart thereof (for example, less than 1 water molecule present for eachmolecule of analogue) can be present.

R Units

R is a substituted or unsubstituted thiazolyl unit having the formula:

R², R³, and R⁴ are substituent groups that can be independently chosenfrom a wide variety of non-carbon atom containing units (for example,hydrogen, hydroxyl, amino, halogen, and nitro) or organic substituentunits, such as substituted and unsubstituted acyclic hydrocarbyl andcyclic hydrocarbyl units as described herein. The carbon comprisingunits can comprise, for example, from 1 to 12 carbon atoms, or 1 to 10carbon atoms, or 1 to 6 carbon atoms.

An example of compounds of Formula (I) include compounds wherein R unitsare thiazol-2-yl units having the formula:

wherein R² and R³ are each independently chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched,        or C₃-C₆ cyclic alkyl;    -   iii) substituted or unsubstituted C₂-C₆ linear, C₃-C₆ branched,        or C₃-C₆ cyclic alkenyl;    -   iv) substituted or unsubstituted C₂-C₆ linear or C₃-C₆ branched        alkynyl;    -   v) substituted or unsubstituted C₆ or C₁₀ aryl;    -   vi) substituted or unsubstituted C₁-C₉ heteroaryl;    -   vii) substituted or unsubstituted C₁-C₉ heterocyclic; or    -   viii) R² and R³ can be taken together to form a saturated or        unsaturated ring having from 5 to 7 atoms; wherein from 1 to 3        atoms can optionally be heteroatoms chosen from oxygen,        nitrogen, and sulfur.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on the R² and R³ units. The followingsubstituents, as well as others not herein described, are eachindependently chosen from:

-   -   i) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl,        alkenyl, and alkynyl; methyl (CO₁), ethyl (C₂), ethenyl (C₂),        ethynyl (C₂), n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃),        3-propenyl (C₃), 1-propenyl (also 2-methylethenyl) (C₃),        isopropenyl (also 2-methylethen-2-yl) (C₃), prop-2-ynyl (also        propargyl) (C₃), propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄),        iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl        (C₄), cyclopentyl (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein;    -   vi) —(CR^(21a)R^(21b))_(p)OR²⁰; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(21a)R^(21b))_(p)C(O)R²⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(21a)R^(21b))_(p)C(O)R²⁰; —CO₂CH₃, —CH₂CO₂CH₃,        —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(21a)R^(21b))_(p)C(O)N(R²⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(21a)R^(21b))_(p)N(R²⁰)²; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) —(CR^(21a)R^(21b))_(p)CN;    -   xiii) —(CR^(21a)R^(21b))_(p)NO₂;    -   xiv) —(CH_(j′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(21a)R^(21b))_(p)SR²⁰; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR_(21a)R_(21b))_(p)SO₂, R²⁰; for example, —SO₂H,        —CH₂SO₂H, —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(21a)R^(21b))_(p)SO₃R²⁰; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R²⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, C₃-C₄ branched, or C₃-C₄ cyclic        alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R²⁰        units can be taken together to form a ring comprising 3-7 atoms;        R^(21a) and R^(21b) are each independently hydrogen or C₁-C₄        linear or C₃-C₄ branched alkyl; the index p is from 0 to 4.

An example of compounds of Formula (I) includes R units having theformula:

wherein R³ is hydrogen and R² is a unit chosen from methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), tert-butyl (C₄), n-pentyl (C₅), 1-methylbutyl (C₅),2-methylbutyl (C₅), 3-methylbutyl (C₅), cyclopropyl (C₃), n-hexyl (C₆),4-methylpentyl (C₆), and cyclohexyl (C₆).

An example of compounds of Formula (I) include R units having theformula:

wherein R² is a unit chosen from methyl (C₁), ethyl (C₂), n-propyl (C₃),iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), andtert-butyl (C₄); and R³ is a unit chosen from methyl (C₁) or ethyl (C₂).Non-limiting examples of this aspect of R includes4,5-dimethylthiazol-2-yl, 4-ethyl-5-methylthiazol-2-yl,4-methyl-5-ethylthiazol-2-yl, and 4,5-diethylthiazol-2-yl.

An example of compounds of Formula (I) includes R units wherein R³ ishydrogen and R² is a substituted alkyl unit, said substitutions chosenfrom:

i) halogen: —F, —Cl, —Br, and —I;

ii) —N(R¹¹)₂; and

iii) —OR¹¹;

wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or C₃-C₄branched alkyl. Non-limiting examples of units that can be a substitutefor a R² or R³ hydrogen atom on R units include —CH₂F, —CHF₂, —CF₃,—CH₂CF₃, —CH₂CH₂CF₃, —CH₂Cl, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —CH₂CH₂OCH₃,—CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).

Further non-limiting examples of units that can be a substitute for a R²or R³ hydrogen atom on R units include 2,2-difluorocyclopropyl,2-methoxycyclohexyl, and 4-chlorocyclohexyl.

An example of compounds of Formula (I), R units include units wherein R³is hydrogen and R² is phenyl or substituted phenyl, wherein non-limitingexamples of R² units include phenyl, 3,4-dimethylphenyl,4-tert-butylphenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl,4-(trifluoromethyl)phenyl, 4-methoxyphenyl, 4-(difluoromethoxy)-phenyl,4-(trifluoromethoxy)phenyl, 3-chloropheny, 4-chlorophenyl, and3,4-dichloro-phenyl, which when incorporated into the definition of Raffords the following R units 4-phenylthiazol-2-yl,3,4-dimethylphenylthiazol-2-yl, 4-tert-butylphenylthiazol-2-yl,4-cyclopropylphenylthiazol-2-yl, 4-diethylaminophenylthiazol-2-yl,4-(trifluoromethyl)-phenylthiazol-2-yl, 4-methoxyphenylthiazol-2-yl,4-(difluoromethoxy)phenylthiazol-2-yl,4-(trifluoromethoxy)phenylthiazol-2-yl, 3-chlorophenylthiazol-2-yl,4-chlorophenylthiazol-2-yl, and 3,4-dichlorophenylthiazol-2-yl.

An example of compounds of Formula (I) includes R units wherein R² ischosen from hydrogen, methyl, ethyl, n-propyl, and iso-propyl and R³ isphenyl or substituted phenyl. A non-limiting example of a R unitaccording to the fifth aspect of the first category of R units includes4-methyl-5-phenylthiazol-2-yl and 4-ethyl-5-phenylthiazol-2-yl.

An example of compounds of Formula (I) includes R units wherein R³ ishydrogen and R² is a substituted or unsubstituted heteroaryl unit chosenfrom 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl,[1,2,3]triazol-5-yl, [1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl,imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,[1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl,furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl,isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, [1,2 ,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.

Further non-limiting example of compounds of Formula (I) includes Runits wherein R² is substituted or unsubstituted thiophen-2-yl, forexample thiophen-2-yl, 5-chlorothiophen-2-yl, and 5-methylthiophen-2-yl.

An example of compounds of Formula (I) includes R units wherein R² issubstituted or unsubstituted thiophen-3-yl, for example thiophen-3-yl,5-chlorothiophen-3-yl, and 5-methylthiophen-3-yl.

An example of compounds of Formula (I) includes R units wherein R² andR³ are taken together to form a saturated or unsaturated ring havingfrom 5 to 7 atoms. Non-limiting examples of the sixth aspect of thefirst category of R units include5,6-dihydro-4H-cyclopentaldlthiazol-2-yl and4,5,6,7-tetrahydrobenzoldlthiazol-2-yl.

Further examples of compounds of Formula (I) include R units that arethiazol-4-yl or thiazol-5-yl units having the formula:

wherein R⁴ is a unit chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched,        or C₃-C₆ cyclic alkyl;    -   iii) substituted or unsubstituted C₂-C₆ linear, C₃-C₆ branched,        or C₃-C₆ cyclic alkenyl;    -   iv) substituted or unsubstituted C₂-C₆ linear or branched        alkynyl;    -   v) substituted or unsubstituted C₆ or C₁₀ aryl;    -   vi) substituted or unsubstituted C₁-C₉ heteroaryl; or    -   vii) substituted or unsubstituted C₁-C₉ heterocyclic.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on the R⁴ units. The following substituents,as well as others not herein described, are each independently chosen:

-   -   i) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl,        alkenyl, and alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂),        ethynyl (C₂), n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃),        3-propenyl (C₃), 1-propenyl (also 2-methylethenyl) (C₃),        isopropenyl (also 2-methylethen-2-yl) (C₃), prop-2-ynyl (also        propargyl) (C₃), propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄),        iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl        (C₄), cyclopentyl (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings;    -   vi) —(CR^(21a)R^(21b))_(p)R²⁰; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(21a)R^(21b))_(p)C(O)R²⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(21a)R^(21b))_(p)C(O)OR²⁰; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(21a)R^(21b))_(p)C(O)N(R²⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(21a)R^(21b))_(p)N(R²⁰)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) —(CR^(21a)R^(21b))_(p)CN;    -   xiii) —(CR^(21a)R^(21b))_(p)NO₂;    -   xiv) —(CH_(j′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(21a)R^(21b))_(p)SR²⁰; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        -SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(21a)R^(21b))_(p)SO₂R²⁰; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR_(21a)R^(21b))_(p)SO₃R²⁰; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R²⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, C₃-C₄ branched, or C₃-C₄ cyclic        alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R²⁰        units can be taken together to form a ring comprising 3-7 atoms;        R^(21a) and R^(21b) are each independently hydrogen or C₁-C₄        linear or C₃-C₄ branched alkyl; the index p is from 0 to 4.

An example of compounds of Formula (I) includes R units wherein R⁴ ishydrogen.

An example of compounds of Formula (I) includes R units wherein R⁴ is aunit chosen from methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl(C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄).Non-limiting examples of this aspect of R includes 2-methylthiazol-4-yl,2-ethylthiazol-4-yl, 2-(n-propyl)thiazol-4-yl, and2-(iso-propyl)thiazol-4-yl.

An example of compounds of Formula (I) includes R units wherein R⁴ issubstituted or unsubstituted phenyl, non-limiting examples of whichinclude phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, and4-methoxyphenyl.

An example of compounds of Formula (I) includes R units wherein R⁴ issubstituted or unsubstituted heteroaryl, non-limiting examples of whichinclude thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl,4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and3-methyl-1,2,4-oxadiazol-5-yl.

Another example of 5-member ring R units includes substituted orunsubstituted imidazolyl units having the formula:

One example of imidazolyl R units includes imidazol-2-yl units havingthe formula:

wherein R² and R³ are each independently chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched,        or C₃-C₆ cyclic alkyl;    -   iii) substituted or unsubstituted C₂-C₆ linear, C₃-C₆ branched,        or C₃-C₆ cyclic alkenyl;    -   iv) substituted or unsubstituted C₂-C₆ linear or branched        alkynyl;    -   v) substituted or unsubstituted C₆ or C₁₀ aryl;    -   vi) substituted or unsubstituted C₁-C₉ heteroaryl;    -   vii) substituted or unsubstituted C₁-C₉ heterocyclic; or    -   viii) R² and R³ can be taken together to form a saturated or        unsaturated ring having from 5 to 7 atoms; wherein from 1 to 3        atoms can optionally be heteroatoms chosen from oxygen,        nitrogen, and sulfur.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on the R² and R³ units. The followingsubstituents, as well as others not herein described, are eachindependently chosen:

-   -   i) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl,        alkenyl, and alkynyl; methyl (CO₁), ethyl (C₂), ethenyl (C₂),        ethynyl (C₂), n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃),        3-propenyl (C₃), 1-propenyl (also 2-methylethenyl) (C₃),        isopropenyl (also 2-methylethen-2-yl) (C₃), prop-2-ynyl (also        propargyl) (C₃), propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄),        iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl        (C₄), cyclopentyl (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein;    -   vi) —(CR^(21a)R^(21b))^(z)OR²⁰; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(21a)R^(21b))^(z)C(O)R²⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(21a)R^(21b))_(z)C(O)OR²⁰; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(21a)R^(21b))_(z)C(O)N(R²⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(21a)R^(21b))_(z)N(R²⁰)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) —(CR^(21a)R^(21b))_(z)CN;    -   xiii) —(CR^(21a)R^(21b))^(z)NO₂;    -   xiv) —(CR_(j′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index j′ is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(21a)R^(21b))_(z)SR²⁰; —SH, —CH₂SH, —CH₂SCH₃, —SC₆H₅,        and —CH₂SC₆H₅;    -   xvi) —(CR^(21a)R^(21b))_(z)SO²⁰; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(21a)R^(21b))_(z)SO₃R²⁰; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃ CH₃, —SO₃C₆H₅ , and —CH₂SO₃ C₆H₅ ;        wherein each R²⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, C₃-C₄ branched, or C₃-C₄ cyclic        alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R²⁰        units can be taken together to form a ring comprising 3-7 atoms;        R^(21a) and R^(21b) are each independently hydrogen or C₁-C₄        linear or C₃-C₄ branched alkyl; the index p is from 0 to 4.

One example of R units includes compounds wherein R units have theformula:

wherein R³ is hydrogen and R² is a unit chosen from methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), and tert-butyl (C₄).

Another example of R units includes compounds wherein R² is a unitchosen from methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃),n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄); andR³ is a unit chosen from methyl (C₁) or ethyl (C₂). Non-limitingexamples of this aspect of R includes 4,5-dimethylimidazol-2-yl,4-ethyl-5-methylimidazol-2-yl, 4-methyl-5-ethylimidazol-2-yl, and4,5-diethylimidazol-2-yl.

An example of R units includes compounds wherein R³ is hydrogen and R²is a substituted alkyl unit chosen, said substitutions chosen from:

i) halogen: —F, —Cl, —Br, and —I;

ii) —N(R¹¹)₂; and

iii) —OR¹¹;

wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or C₃-C₄branched alkyl.

Non-limiting examples of units comprising this embodiment of R includes:—CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂Cl, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).

An example of R units includes units wherein R³ is hydrogen and R² isphenyl.

An example of R units includes units wherein R³ is hydrogen and R² is aheteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, 1,2,3 ltriazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,410 xadiazol-3-yl,1,2,410 xadiazol-5-yl, 1,3,410 xadiazol-2-yl, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.

Z Units

Z is a unit having the formula:

—(L)_(n)—R¹

R¹ is chosen from:

-   -   i) hydrogen;    -   ii) hydroxyl;    -   iii) amino;    -   iv) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched or        C₃-C₆ cyclic alkyl;    -   v) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched o        C₃-C₆r cyclic alkoxy;    -   vi) substituted or unsubstituted C₆ or C₁₀ aryl;    -   vii) substituted or unsubstituted C₁-C₉ heterocyclic rings; or    -   viii) substituted or unsubstituted C₁-C₉ heteroaryl rings.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on the R¹ units. The following substituents,as well as others not herein described, are each independently chosen:

-   -   i) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl,        alkenyl, and alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂),        ethynyl (C₂), n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃),        3-propenyl (C₃), 1-propenyl (also 2-methylethenyl) (C₃),        isopropenyl (also 2-methylethen-2-yl) (C₃), prop-2-ynyl (also        propargyl) (C₃), propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄),        iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl        (C₄), cyclopentyl (C₅), cyclohexyl (C6);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein;    -   vi) —(CR^(31a)R^(31b))_(q)OR^(30;) for example, —OH, —CH₂OH,        —OCH₃, —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(31a)R^(31b))^(q)C(O)R³⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(31a)R^(31b))_(q)C(O)OR³⁰; for example, —CO₂CH₃,        CH₂CO₂CH₃ , —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(31a)R^(31b))_(q)C(O)N(R³⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(31a)R^(31b))_(q)N(R³⁰)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   —(CR^(31a)R^(31b))_(q)CN;    -   xiii) —(CR^(31a)R^(31b))_(q)NO₂;    -   xiv) —(CH_(J′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(31a)R^(31b))_(q)SR³⁰; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        -SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(31a)R^(31b))_(q)SO₂R³⁰; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅ , and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(31a)R^(31b))^(c)SO₃R³⁰; for example, —SO₃ H,        —CH₂SO₃H, —SO₃ CH₃, —CH₂SO₃CH₃—SO₃ C₆H₅ , and —CH₂SO₃C₆H₅ ;        wherein each R³⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic        alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R³⁰        units can be taken together to form a ring comprising 3-7 atoms;        R^(31a) and R^(31b) are each independently hydrogen or C₁-C₄        linear or C₃-C₄ branched alkyl; the index q is from 0 to 4.

One example of R¹ units includes substituted or unsubstituted phenyl (C₆aryl) units, wherein each substitution is independently chosen from:halogen, C₁-C₄ linear, branched alkyl, or cyclic alkyl, —OR¹¹, —CN,—N(R¹¹)₂, —CO₂R¹¹, —C(O)N(R¹¹)₂, —NR¹¹C(O)R¹¹, —NO₂, and —SO₂R¹¹; eachR¹¹ is independently hydrogen; substituted or unsubstituted linear,C₃-C₄ branched, C₃-C₄ cyclic alkyl, alkenyl, or alkynyl; substituted orunsubstituted phenyl or benzyl; or two R¹¹ units can be taken togetherto form a ring comprising from 3-7 atoms.

An example of R¹ units includes substituted C₆ aryl units chosen fromphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and3,5-dimethoxyphenyl.

An example of R¹ units includes substituted or unsubstituted C₆ arylunits chosen from 2,4-difluorophenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl,2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl,2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5-trichlorophenyl, and2,4,6-trichlorophenyl.

An example of R¹ units includes substituted C₆ aryl units chosen from2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl,2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl,3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl,2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl,2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl,2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl,3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl,2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl,2-isopropylphenyl, 3-isopropylphenyl, and 4-isopropylphenyl.

An example of R¹ units includes substituted C₆ aryl units chosen from2-aminophenyl, 2-(N-methylamino)phenyl, 2-(N,N-dimethylamino)phenyl,2-(N-ethylamino)phenyl, 2-(N,N-diethylamino)phenyl, 3-aminophenyl,3-(N-methylamino)phenyl, 3-(N,N-dimethylamino)phenyl,3-(N-ethylamino)phenyl, 3-(N,N-diethylamino)phenyl, 4-aminophenyl,4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl,4-(N-ethylamino)phenyl, and 4-(N,N-diethylamino)phenyl.

R¹ can comprise heteroaryl units. Non-limiting examples of C₁-C₉heteroaryl units include:

R¹ heteroaryl units can be substituted or unsubstituted. Non-limitingexamples of units that can substitute for hydrogen include units chosenfrom:

i) C₁-C₆ linear, C₃-C₆ branched, and C₃-C₆ cyclic alkyl;

ii) substituted or unsubstituted phenyl and benzyl;

iii) substituted of unsubstituted C₁-C₉ heteroaryl;

iv) —C(O)R⁹; and

v) —NHC(O)R⁹;

wherein R⁹ is C₁-C₆ linear and branched alkyl; C₁-C₆ linear and C₃-C₆branched alkoxy; or —NHCH₂C(O)R¹⁰; R¹⁰ is chosen from hydrogen, methyl,ethyl, and tert-butyl.

An example of R¹ relates to units substituted by an alkyl unit chosenfrom methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,and tert-butyl.

An example of R¹ includes units that are substituted by substituted orunsubstituted phenyl and benzyl, wherein the phenyl and benzylsubstitutions are chosen from one or more:

i) halogen;

ii) C₁-C₃ alkyl;

iii) C₁-C₃ alkoxy;

iv) —CO₂R¹¹; and

v) —NHCOR¹⁶;

wherein R^(H) and R¹⁶ are each independently hydrogen, methyl, or ethyl.

An example of R¹ relates to phenyl and benzyl units substituted by acarboxy unit having the formula —C(O)R⁹; R⁹ is chosen from methyl,methoxy, ethyl, and ethoxy.

An example of R¹ includes phenyl and benzyl units substituted by anamide unit having the formula —NHC(O)R⁹; R⁹ is chosen from methyl,methoxy, ethyl, ethoxy, tert-butyl, and tert-butoxy.

An example of R¹ includes phenyl and benzyl units substituted by one ormore fluoro or chloro units.

L Units

L is a linking unit which is present when the index n is equal to 1, butis absent when the index n is equal to 0. L units have the formula:

—[Q]_(y)[C(R^(5a)R^(5b))]_(x)[Q¹]_(z)[C(R^(6a)R^(6b))]_(w)—

wherein Q and Q¹ are each independently:

i) —C(O)—;

ii) —NH—;

iii) —C(O)NH—;

iv) —NHC(O)—;

v) —NHC(O)NH—;

vi) —NHC(O)O—;

vii) —C(O)O—;

viii) —C(O)NHC(O)—;

ix) —O—;

x) —S—;

xi) —SO₂—;

xii) —C(═NH)—;

xiii) —C(═NH)NH—;

xiv) —NHC(═NH)—; or

xv) —NHC(═NH)NH—.

When the index y is equal to 1, Q is present. When the index y is equalto 0, Q is absent. When the index z is equal to 1, Q¹ is present. Whenthe index z is equal to 0, Q¹ is absent.

R^(5a) and R^(5b) are each independently:

i) hydrogen;

ii) hydroxy;

iii) halogen;

iv) substituted or unsubstituted C₁-C₆ linear or C₃-C₆ branched alkyl;or

v) a unit having the formula:

—[C(R^(7a)R^(7b))]_(t)R⁸

wherein R^(7a) and R^(7b) are each independently:

i) hydrogen; or

ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆cyclic alkyl.

R⁸ is:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆cyclic alkyl;

iii) substituted or unsubstituted C₆ or C₁₀ aryl;

iv) substituted or unsubstituted C₁-0₀ heteroaryl; or

v) substituted or unsubstituted C₁-0₀ heterocyclic.

R^(6a) and R^(6b) are each independently:

i) hydrogen; or

ii) C₁-C₄ linear or C₃-C₄ branched alkyl.

The indices t, w and x are each independently from 0 to 4.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on R^(5a), R^(5b), R^(7a), R^(7b), and R⁸units. The following substituents, as well as others not hereindescribed, are each independently chosen:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂), ethynyl (C₂),        n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), 3-propenyl        (C₃), 1-propenyl (also 2-methylethenyl) (C₃), isopropenyl (also        2-methylethen-2-yl) (C₃), prop-2-ynyl (also propargyl) (C₃),        propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),        tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl        (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein below;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein below;    -   vi) —(CR^(41a)C^(41b))_(r)OR⁴⁰; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) (CR^(41a)R^(41b))_(r)C(O)R⁴⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(41a)R^(41b))_(r)C(O)OR⁴⁰; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(C_(41a)R^(41b))_(r)C(O)N(R⁴⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) (CR^(41a)R^(41b))_(r)N(R⁴⁰)₂ ; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) (CR^(41a) R^(41b))_(r)CN;    -   xiii) (CR^(41a)R^(41b))_(r)NO₂;    -   xiv) —(CR_(j′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(41a)R^(41b))_(r)SR⁴⁰; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        -SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(41a)R^(41b))_(r)SO₂R⁴⁰; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(41a)R^(41b))_(r)SO₃R⁴⁰; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R⁴⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic        alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R⁴⁰        units can be taken together to form a ring comprising 3-7 atoms;        R ^(41a) and R^(41b) are each independently hydrogen or C₁-C₄        linear or C₃-C₄ branched alkyl; the index r is from 0 to 4.

One aspect of L units relates to units having the formula:

—C(O)[C(R^(5a)R^(5b))]_(x)NHC(O)—

wherein R^(5a) is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted phenyl, and substituted or unsubstitutedheteroaryl; and the index x is 1 or 2. Some embodiments relate tolinking units having the formula:

i) —C(O)[C(R^(5a)H)]NHC(O)O—;

ii) —C(O)[C(R^(5a)H)][CH₂]NHC(O)O—;

ii) —C(O)[CH₂][C(R^(5a)H)]NHC(O)O—;

iv) —C(O)[C(R^(5a)H)]NHC(O)—;

v) —C(O)[C(R^(5a)H)][CH₂]NHC(O)—; or

vi) —C(O)[CH₂][C(R^(5a)H)]NHC(O)—;

wherein R^(5a) is:

i) hydrogen;

ii) methyl;

iii) ethyl;

iv) isopropyl;

v) phenyl;

vi) benzyl;

vii) 4-hydroxybenzyl;

viii) hydroxymethyl; or

ix) 1-hydroxyethyl.

When the index x is equal to 1, this embodiment provides the followingnon-limiting examples of L units:

When the index x is equal to 2, this embodiment provides the followingnon-limiting examples of L units:

Another embodiment of L units includes units wherein Q is —C(O)—, theindices x and z are equal to 0, w is equal to 1 or 2, a first R^(6a)unit chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and3,5-dimethoxyphenyl; a second R^(6a) unit is hydrogen and R^(6b) unitsare hydrogen. For example a linking unit having the formula:

An example of this embodiment of L includes a first R^(6a) unit asdepicted herein above that is a substituted or unsubstituted heteroarylunit as described herein above.

An example of this embodiment of L includes units having the formula:

—C(O)[C(R^(6a)R^(6b))]₉—;

wherein R^(6a) and R^(6b) are hydrogen and the index w is equal to 1 or2; said units chosen from:

i) —C(O)CH₂—; and

ii) —C(O)CH₂CH₂—.

Another embodiment of L units includes units having the formula:

—C(O)[C(R^(5a)R^(5b))]_(x)C(O)—;

wherein R^(5a) and R^(5b) are hydrogen and the index x is equal to 1 or2; said units chosen from:

i) —C(O)CH₂C(O)—; and

ii) —C(O)CH₂CH₂C(O)—.

Another embodiment of L units includes units having the formula:

—C(O)NH[C(R^(5a)R^(5b))]_(x)—;

wherein R^(5a) and R^(5b) are hydrogen and the index w is equal to 0, 1or 2; said units chosen from:

ii) —C(O)NH—;

ii) —C(O)NHCH₂—; and

iii) —C(O)NHCH₂CH₂—.

An example of L units includes units having the formula:

—SO₂[C(R^(6a)R^(6b))]_(w)—;

wherein R^(8a) and R^(8b) are hydrogen or methyl and the index w isequal to 0, 1 or 2; said units chosen from:

i) —SO₂—;

ii) —SO₂CH₂—; and

iii) —SO₂CH₂CH₂—.

Synthetic Schema.

Disclosed herein are categories of compounds useful for the methodsdescribed herein, and pharmaceutically acceptable salt forms thereof.For example, a compound having the formula:

can form salts, for example, a salt of the sulfamic acid:

The compounds can also exist in a zwitterionic form, for example:

as a salt of a strong acid, for example:

An aspect of Category I of the present disclosure relates to compoundswherein R is a substituted or unsubstituted thiazol-2-yl unit having theformula:

one embodiment of which relates to inhibitors having the formula:

wherein R units are thiazol-2-yl units, that when substituted, aresubstituted with R² and R³ units. R and R^(5a) units are furtherdescribed in Table I.

TABLE I No. R R^(5a) A1 thiazol-2-yl (S)-benzyl A2 4-methylthiazol-2-yl(S)-benzyl A3 4-ethylthiazol-2-yl (S)-benzyl A4 4-propylthiazol-2-yl(S)-benzyl A5 4-iso-propylthiazol-2-yl (S)-benzyl A64-cyclopropylthiazol-2-yl (S)-benzyl A7 4-butylthiazol-2-yl (S)-benzylA8 4-tert-butylthiazol-2-yl (S)-benzyl A9 4-cyclohexythiazol-2-yl(S)-benzyl A10 4-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl A114-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl A124-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl A134-(methoxymethyl)thiazol-2-yl (S)-benzyl A14 4-(carboxylic acid ethylester)thiazol-2-yl (S)-benzyl A15 4,5-dimethylthiazol-2-yl (S)-benzylA16 4-methyl-5-ethylthiazol-2-yl (S)-benzyl A17 4-phenylthiazol-2-yl(S)-benzyl A18 4-(4-chlorophenyl)thiazol-2-yl (S)-benzyl A194-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl A204-methyl-5-phenylthiazol-2-yl (S)-benzyl A214-(thiophen-2-yl)thiazol-2-yl (S)-benzyl A224-(thiophen-3-yl)thiazol-2-yl (S)-benzyl A234-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzyl A245,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl A254,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl

The compounds encompassed within the first aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in Scheme Iand described in Example 1 below.

EXAMPLE 14-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (5)

Preparation of [1-(S)-carbamoyl-2-(4-nitrophenyl) ethyl-carbamic acidtert-butyl ester (1): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid andN-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added dropwiseiso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at0° C. for 20 minutes after which NH₃ (g) is passed through the reactionmixture for 30 minutes at 0° C. The reaction mixture is concentrated andthe residue dissolved in EtOAc, washed successively with 5% citric acid,water, 5% NaHCO₃, water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to a residue that is triturated with a mixture ofEtOAc/petroleum ether to provide 2.2 g (74%) of the desired product as awhite solid.

Preparation of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]carbamic acidtert-butyl ester (2): To a solution of[1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl]-carbamic acid tert-butyl ester,1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson's reagent(0.262 g. 0.65 mmol). The reaction mixture is stirred for 3 hours andconcentrated to a residue which is purified over silica to provide 0.350g (83%) of the desired product. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H),8.10 (d. J=8.4 Hz, 2H), 8.01 (s, 1H), 7.42 (d, J=8.4 Hz, 2H), 5.70 (d,J=7.2 Hz, 1H), 4.85 (d, J=7.2 Hz, 1H), 3.11-3.30 (m, 1H), 1.21 (s, 9H).

Preparation of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine(3): A mixture of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamicacid tert-butyl ester, 2, (0.245 g, 0.753 mmol), 1-bromo-2-butanone(0.125 g, 0.828 mmol) in CH₃CN (5 mL) is refluxed 3 hours. The reactionmixture is cooled to room temperature and diethyl ether is added to thesolution and the precipitate which forms is removed by filtration. Thesolid is dried under vacuum to afford 0.242 g (90% yield) of the desiredproduct. ESI+MS 278 (M+1).

Preparation of{1-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-phenylethyl}carbamicacid tert-butyl ester (4): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.393 g, 1.1 mmol),(S)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid (0.220 g, 0.828mmol) and 1-hydroxybenzotriazole (HOBt) (0.127 g, 0.828 mmol) in DMF (10mL) at 0° C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDCI) (0.159 g, 0.828 mmol) followed by diisopropylamine (0.204 g, 1.58mmol). The mixture is stirred at 0° C. for 30 minutes then at roomtemperature overnight. The reaction mixture is diluted with water andextracted with EtOAc. The combined organic phase is washed with 1 Naqueous HCl, 5% aqueous NaHCO₃, water and brine, and dried over Na₂SO₄.The solvent is removed in vacuo to afford 0.345 g of the desired productwhich is used without further purification. LC/MS ESI+525 (M+1).

Preparation of4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid ammonium salt (5):{1-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-phenylethyl}carbamicacid tert-butyl ester, 4, (0.345 g) is dissolved in MeOH (4 mL). Acatalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 2 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (12 mL) and treatedwith SO₃-pyridine (0.314 g). The reaction is stirred at room temperaturefor 5 minutes after which a 7% solution of NH₄OH (50 mL) is added. Themixture is then concentrated and the resulting residue is purified byreverse phase chromatography to afford 0.222 g of the desired product asthe ammonium salt. ¹H NMR (CD₃OD δ 7.50-6.72 (m, 10H), 5.44-5.42 (d, 1H,J=6.0 Hz), 4.34 (s, 1H), 3.34-2.79 (m, 4H), 2.83-2.76 (q, 2H, J=7.2 Hz),1.40 (s, 9H), 1.31 (t, 3H, J=7.5 Hz).

The disclosed inhibitors can also be isolated as the free acid. Anon-limiting example of this procedure is described herein below inExample 4.

The following is a non-limiting example of compounds encompassed withinthis embodiment of the first aspect of Category I of the presentdisclosure.

4-{(S)-2-[(R)-2-(tert-butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD δ 7.22-7.02 (m, 10H), 5.39 (s, 1H), 4.34 (s, 1H),3.24-2.68 (m, 6H), 1.37 (s, 9H), 1.30 (t, 3H, J=7.5 Hz).

Another embodiment of this aspect of Category I relates to inhibitorshaving the formula:

wherein R units and R^(5a) units further described in Table II.

TABLE II No. R R^(5a) B26 thiazol-2-yl (S)-benzyl B274-methylthiazol-2-yl (S)-benzyl B28 4-ethylthiazol-2-yl (S)-benzyl B294-propylthiazol-2-yl (S)-benzyl B30 4-iso-propylthiazol-2-yl (S)-benzylB31 4-cyclopropylthiazol-2-yl (S)-benzyl B32 4-butylthiazol-2-yl(S)-benzyl B33 4-tert-butylthiazol-2-yl (S)-benzyl B344-cyclohexylthiazol-2-yl (S)-benzyl B354-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl B364-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl B374-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl B384-(methoxymethyl)thiazol-2-yl (S)-benzyl B39 4-(carboxylic acid ethylester)thiazol-2-yl (S)-benzyl B40 4,5-dimethylthiazol-2-yl (S)-benzylB41 4-methyl-5-ethylthiazol-2-yl (S)-benzyl B42 4-phenylthiazol-2-yl(S)-benzyl B43 4-(4-chlorophenyl)thiazol-2-yl (S)-benzyl B444-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl B454-methyl-5-phenylthiazol-2-yl (S)-benzyl B464-(thiophen-2-yl)thiazol-2-yl (S)-benzyl B474-(thiophen-3-yl)thiazol-2-yl (S)-benzyl B484-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzyl B495,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl B504,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl

The compounds of this embodiment can be prepared according to theprocedure outlined above in Scheme I and described in Example 1 bysubstituting the appropriate Boc-δ-amino acid for(S)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid in step (d).

The following are non-limiting examples of compounds according to thisembodiment.

{1-[1-(4-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methylcarbamic acid tert-butyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 8.36 (d,J=8.1 Hz, 1H), 7.04-7.22 (m, 9H), 5.45 (s, 1H), 3.01-3.26 (m, 2H),2.60-2.88 (m, 4H), 2.33 (s, 3H), 1.30 (s, 9H).

{1-[1-(4-Phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methylcarbamic acid tert-butyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 8.20 (d,J=8.1 Hz, 1H), 7.96-7.99 (m, 2H), 7.48-7.52 (m, 3H), 7.00-7.23(m, 7H),6.89 (s, 1H), 5.28 (q, J=7.5 Hz, 1H), 4.33 (t, J=6.6 Hz, 1H), 3.09-3.26(m, 2H), 3.34 (dd, J=13.2 and 8.4 Hz, 1H), 2.82 (dd, J=13.2 and 8.4 Hz,1H), 1.38 (s, 9H).

The second aspect of Category I of the present disclosure relates tocompounds wherein R is a substituted or unsubstituted thiazol-4-ylhaving the formula:

one embodiment of which relates to inhibitors having the formula:

wherein R units and Ry^(a) units further described in Table III.

TABLE III No. R R^(5a) C51 thiazol-4-yl (S)-benzyl C522-methylthiazol-4-yl (S)-benzyl C53 2-ethylthiazol-4-yl (S)-benzyl C542-propylthiazol-4-yl (S)-benzyl C55 2-iso-propylthiazol-4-yl (S)-benzylC56 2-cyclopropylthiazol-4-yl (S)-benzyl C57 2-butylthiazol-4-yl(S)-benzyl C58 2-tert-butylthiazol-4-yl (S)-benzyl C592-cyclohexylthiazol-4-yl (S)-benzyl C602-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzyl C612-(3,3,3-trifluoropropyl)thiazol-4-yl (S)-benzyl C622-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzyl C632-phenylthiazol-4-yl (S)-benzyl C64 2-(4-chlorophenyl)thiazol-4-yl(S)-benzyl C65 2-(3,4-dimethylphenyl)thiazol-4-yl (S)-benzyl C662-(thiophen-2-yl)thiazol-4-yl (S)-benzyl C672-(thiophen-3-yl)thiazol-4-yl (S)-benzyl C682-(3-chlorothiophen-2-yl)thiazol-4-yl (S)-benzyl C692-(3-methylthiophen-2-yl)thiazol-4-yl (S)-benzyl C702-(2-methylthiazol-4-yl)thiazol-4-yl (S)-benzyl C712-(furan-2-yl)thiazol-4-yl (S)-benzyl C72 2-(pyrazin-2-yl)thiazol-4-yl(S)-benzyl C73 2-[(2-methyl)pyridin-5-yl]thiazol-4-yl (S)-benzyl C742-(4-chlorobenzenesulfonylmethyl)thiazol-4-yl (S)-benzyl C752-(tert-butylsulfonylmethyl)thiazol-4-yl (S)-benzyl

The compounds encompassed within the second aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in SchemeII and described in Example 2 herein below.

EXAMPLE 24-{(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido-2-(2-phenylthiazol-4-yl)}phenylsulfamicacid (9)

Preparation of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamicacid tert-butyl ester (6): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g,4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). Thereaction mixture is stirred at 0° C. for 20 minutes and filtered. Thefiltrate is treated with an ether solution of diazomethane (˜16 mmol) at0° C. The reaction mixture is stirred at room temperature for 3 hoursthen concentrated in vacuo. The resulting residue is dissolved in EtOAcand washed successively with water and brine, dried (Na₂SO₄), filteredand concentrated. The residue is purified over silica (hexane/EtOAc 2:1)to afford 1.1 g (82% yield) of the desired product as a slightly yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd,J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).

Preparation of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate (7): To a 0° C.solution of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is addeddropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture isstirred at 0° C. for 1.5 hours then the reaction is quenched at 0° C.with sat. Na₂CO₃. The mixture is extracted with EtOAc (3× 25 mL) and thecombined organic extracts are washed with brine, dried (Na₂SO₄),filtered and concentrated to obtain 0.400 g of the product which is usedin the next step without further purification. ¹H NMR (300 MHz, CDCl₃) δ8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H),4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of tert-butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate(8): A mixture of thiobenzamide (0.117 g, 0.85 mmol) and (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (0.300 g, 0.77mmol) in CH₃CN (4 mL) is refluxed 2 hours. The reaction mixture iscooled to room temperature and diethyl ether is added to precipitate theintermediate 2-(nitrophenyl)-(S)-1-(4-phenylthiazol-2-yl)ethylaminewhich is isolated by filtration as the hydrobromide salt. Thehydrobromide salt is dissolved in DMF (3 mL) together withdiisoproylethylamine (0.42 mL, 2.31 mmol), 1-hydroxybenzotriazole (0.118g, 0.79 mmol) and (S)-(2-tert-butoxycarbonyl-amino)-3-phenylpropionicacid (0.212 g, 0.80 mmol). The mixture is stirred at 0° C. for 30minutes then at room temperature overnight. The reaction mixture isdiluted with water and extracted with EtOAc. The combined organic phaseis washed with 1 N aqueous HCl, 5% aqueous NaHCO₃, water and brine, anddried over Na₂SO₄. The solvent is removed in vacuo to afford 0.395 g(90% yield) of the desired product which is used without furtherpurification. LC/MS ESI+573 (M+1).

Preparation of4-{(S)-2-(S)-2-(tert-butoxycarbonyl)-3-phenylpropaneamido-2-(2-phenylthiazole-4-yl)}phenylsulfamicacid (9): tert-butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,8, (0.360 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 12 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.296 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH (10 mL) is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.050 g of the desired product as the ammoniumsalt. ¹H NMR (300 MHz, MeOH-d₄) δ 8.20 (d, J=8.1 Hz, 1H), 7.96-7.99 (m,2H), 7.48-7.52 (m, 3H), 7.00-7.23(m, 7H), 6.89 (s, 1H), 5.28 (q, J=7.5Hz, 1H), 4.33 (t, J=6.6 Hz, 1H), 3.09-3.26 (m, 2H), 3.34 (dd, J=13.2 and8.4 Hz, 1H), 2.82 (dd, J=13.2 and 8.4 Hz, 1H), 1.38 (s, 9H).

An aspect of Category II of the present disclosure relates to compoundswherein R is a substituted or unsubstituted thiazol-4-yl unit having theformula:

one embodiment of which relates to inhibitors having the formula:

wherein R units are thiazol-4-yl units, that when substituted, aresubstituted with R⁴ units. R and R^(5a) units are further described inTable IV.

TABLE IV No. R R^(5a) D76 thiazol-4-yl (S)-benzyl D772-methylthiazol-4-yl (S)-benzyl D78 2-ethylthiazol-4-yl (S)-benzyl D792-propylthiazol-4-yl (S)-benzyl D80 2-iso-propylthiazol-4-yl (S)-benzylD81 2-cyclopropylthiazol-4-yl (S)-benzyl D82 2-butylthiazol-4-yl(S)-benzyl D83 2-tert-butylthiazol-4-yl (S)-benzyl D842-cyclohexylthiazol-4-yl (S)-benzyl D852-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzyl D862-(3,3,3-trifluoropropyl)thiazol-4-yl (S)-benzyl D872-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzyl D882-phenylthiazol-4-yl (S)-benzyl D89 2-(4-chlorophenyl)thiazol-4-yl(S)-benzyl D90 2-(3,4-dimethylphenyl)thiazol-4-yl (S)-benzyl D912-(thiophen-2-yl)thiazol-4-yl (S)-benzyl D922-(thiophen-3-yl)thiazol-4-yl (S)-benzyl D932-(3-chlorothiophen-2-yl)thiazol-4-yl (S)-benzyl D942-(3-methylthiophen-2-yl)thiazol-4-yl (S)-benzyl D952-(2-methylthiazol-4-yl)thiazol-4-yl (S)-benzyl D962-(furan-2-yl)thiazol-4-yl (S)-benzyl D97 2-(pyrazin-2-yl)thiazol-4-yl(S)-benzyl D98 2-[(2-methyl)pyridin-5-yl]thiazol-4-yl (S)-benzyl D992-(4-chlorobenzenesulfonylmethyl)thiazol-4-yl (S)-benzyl D1002-(tert-butylsulfonylmethyl)thiazol-4-yl (S)-benzyl

The compounds encompassed within the second aspect of Category II of thepresent disclosure can be prepared by the procedure outlined in SchemeIII and described in Example 3 herein below.

EXAMPLE 34-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamic acid (13)

Preparation of methyl(S)-1-[(S)-1-(2-ethylthiazole-4-yl)-2-(4-nitrophenyl)-ethyl]amino-1-oxo-3-phenylpropane-2-ylcarbamate(12): A mixture of propanethioamide (69 mg, 0.78 mmol) and(S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7,(0.300 g, 0.77 mmol) in CH₃CN (4 mL) is refluxed for 2 hours. Thereaction mixture is cooled to room temperature and diethyl ether isadded to precipitate the intermediate2-(nitrophenyl)-(S)-1-(4-ethylthiazol-2-yl)ethylamine which is isolatedby filtration as the hydrobromide salt. The hydrobromide salt isdissolved in DMF (8 mL) together with diisoproylethylamine (0.38 mL,2.13 mmol), 1-hydroxybenzotriazole (107 mg, 0.71 mmol) and(S)-(2-methoxycarbonyl-amino)-3-phenylpropionic acid (175 mg, 0.78mmol). The mixture is stirred at 0° C. for 30 minutes then at roomtemperature overnight. The reaction mixture is diluted with water andextracted with EtOAc. The combined organic phase is washed with 1 Naqueous HCl, 5% aqueous NaHCO₃, water and brine, and dried over Na₂SO₄.The solvent is removed in vacuo to afford 0.300 g (81% yield) of thedesired product which is used without further purification. LC/MS ESI+MS483 (M+1).

Preparation of4-((S)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamic acid ammonium salt (13): tert-Butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,12, (0.300 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(223 mg, 1.40 mmol). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH (12 mL) is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford 25 mg of the desired product as theammonium salt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.14-7.24 (m, 6H), 6.97-7.0(m, 4H), 6.62 (s, 1H), 5.10-5.30 (μ, 1H), 4.36 (t, J=7.2 Hz, 1H), 3.63(s, 3H), 3.14 (dd, J=13.5 and 6.3 Hz, 1H), 2.93-3.07 (m, 5H), 2.81 (dd,J=13.5 and 6.3 HZ, 1H), 1.39 (t, J=7.8 Hz, 3H).

In another iteration of the process of the present disclosure, compound13, as well as the other analogues which comprise the presentdisclosure, can be isolated as the free acid by adapting the proceduredescribed herein below.

EXAMPLE 44-((S)-2-((S)-2-(Methoxycarbonylamino)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamic acid [Free Acid Form] (13)

Preparation of {1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-phenylethyl}-carbamicacid methyl ester (12a): A Parr hydrogenation vessel is charged withtert-butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,12, (18.05 g, 37.4 mmol, 1.0 eq) and Pd/C (10% Pd on C, 50% wet,Degussa-type E101 NE/W, 2.68 g, 15 wt %) as solids. MeOH (270 mL, 15mL/g) is added to provide a suspension. The vessel is put on a Parrhydrogenation apparatus. The vessel is submitted to a fill/vacuumevacuate process with N₂ (3×20 psi) to inert, followed by the sameprocedure with H₂ (3×40 psi). The vessel is filled with H₂ and thevessel is shaken under 40 psi H₂ for ˜40 hr. The vessel is evacuated andthe atmosphere is purged with N₂ (5×20 psi). An aliquot is filtered andanalyzed by HPLC to insure complete conversion. The suspension isfiltered through a pad of celite to remove the catalyst, and thehomogeneous yellow filtrate is concentrated by rotary evaporation toafford 16.06 g (95% yield) of the desired product as a tan solid, whichis used without further purification.

Preparation of4-((S)-2-((S)-2-(methoxycarbonyl)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamic acid (13): A 100 mL RBF is charged with{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-phenylethyl}-carbamicacid methyl ester, 12a, (10.36 g, 22.9 mmol, 1.0 eq.) prepared in thestep described herein above. Acetonitrile (50 mL, 5 mL/g) is added andthe yellow suspension is stirred at room temperature. A second 3-necked500 mL RBF is charged with SO₃.pyr (5.13 g, 32.2 mmol, 1.4 eq.) andacetonitrile (50 mL 5 mL/g) and the white suspension is stirred at roomtemperature. Both suspensions are gently heated until the reactionsolution containing {1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-4yl)ethyl-carbamoyl]-2-phenylethyl}-carbamic acid methyl ester becomesred-orange in color (typically for this example about 44° C.). Thissubstrate containing solution is poured in one portion into the stirringsuspension of SO₃.pyr at 35° C. The resulting opaque mixture (39° C.) isstirred vigorously while allowed to slowly cool to room temperature.After stirring for 45 min, the reaction is determined to be complete byHPLC. H₂O (200 mL, 20 mL/g) is added to the orange suspension to providea yellow-orange homogeneous solution having a pH of approximately 2.4.Concentrated H₃PO₄ is added slowly over 12 minutes to lower the pH toapproximately 1.4. During this pH adjustment, an off-white precipitateis formed and the solution is stirred at room temperature for 1 hr. Thesuspension is filtered and the filter cake is washed with the filtrate.The filter cake is air-dried on the filter overnight to afford 10.89 g(89% yield) of the desired product as a tan solid.

The following are further non-limiting examples of the second aspect ofCategory II of the present disclosure.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-methylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.15 (d, J=8.4 Hz, 1H), 7.16-7.25 (m,5H), 6.97-7.10 (m, 4H), 6.61 (s, 1H), 5.00-5.24 (m, 1H), 4.36 (t, J=7.2Hz, 1H), 3.64 (s, 3H), 3.11-3.19 (s, 1H), 2.92-3.04 (s, 2H), 2.81 (dd,J=13.5 and 8.1 Hz, 1H), 2.75 (s, 3H).

4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.16-7.29 (m, 5H), 7.02-7.12 (m, 4H),6.83 (s, 1H), 5.10-5.35 (m, 1H), 3.52-3.67(m, 3H), 3.18-3.25 (m, 2H),3.05 (q, J=7.5 Hz, 2H), 2.82-2.95 (m, 2H), 2.65 (s, 3H), 1.39 (t, J=7.5Hz, 3H).

4-{(S)-2-(2-Isopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.16 (d, 1H, J=8.7 Hz), 7.22-7.13 (m, 3H), 7.07(d, 1H, J=8.4 Hz), 6.96 (d, 1H, J=8.1 Hz), 6.62 (s, 1H), 5.19 (t, 1H,J=7.2 Hz), 4.36 (t, 1H, J=7.8 Hz), 3.63 (s, 3H), 3.08 (1H, A of ABX,J=3.6, 14.5 Hz), 2.99 (1H, B of ABX, J=7.2, 13.8 Hz), 2.85-2.78 (m, 1H),1.41 (d, 6H, J=6.9 Hz).

4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid: ¹H NMR(CD₃OD): δ 7.15-7.02 (m, 5H), 6.96-6.93 (d, 2H, J=8.4 Hz), 6.86-6.83 (d,2H, J=8.3 Hz), 6.39 (s, 1H), 5.01 (t, 1H, J=5.0 Hz), 4.22 (t, 1H, J=7.4Hz), 3.51 (s, 3H), 2.98-2.69 (m, 2H), 2.22-2.21 (m, 1H), 1.06-1.02 (m,2H), 0.92-0.88 (m, 2H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamido]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamicacid: ¹H NMP (300 MHz, DMSO-d₆) δ 7.96-7.99 (m, 2H), 7.51-7.56 (m, 3H),7.13-7.38 (m, 6H), 6.92-6.95 (m, 4H), 5.11-5.16 (m, 1H), 4.32-4.35 (m,1H), 3.51 (s, 3H), 3.39-3.40 (m, 2H), 3.09-3.19 (m, 1H), 2.92-3.02 (m,2H), 2.75 (dd, J=10.5 Hz and 9.9 Hz, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.61-7.56 (m, 2H), 7.25-7.01 (m, 10H), 6.75 (s,1H), 5.24-5.21 (q, 1H, J=7.2 Hz), 4.38 (t, 1H, J=7.2 Hz), 3.60 (s, 3H),3.23-3.14 (m, 1H), 3.08-3.00 (m, 2H), 2.87-2.80 (m, 1H).

4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.78-7.76 (d, 1H, J=5.4 Hz), 7.36-7.14 (m, 10H),7.03 (s, 1H), 5.39 (t, 1H, J=6.9 Hz), 4.54 (t, 1H, J=7.3 Hz), 3.80 (s,3H), 3.39-2.98 (m, 4H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.38 (d, 1H, J=5.1 Hz), 7.15-6.93 (m, 10H), 6.73(s, 1H), 5.17 (t, 1H, J=6.9 Hz), 4.31 (t, 1H, J=7.3 Hz), 3.57 (s, 3H),3.18-3.11 (m, 1H), 3.02-2.94 (m, 2H), 2.80-2.73 (m, 1H), 2.46 (s, 3H).

4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.54-7.46 (m, 1H), 7.02-6.79 (m, 10H), 6.55-6.51(m, 1H), 6.44-6.41 (m, 1H), 5.02-5.00 (q, 1H, J=6.4 Hz), 4.16-4.14 (q,1H, J=7.1 Hz), 3.43 (s, 3H), 2.96-2.58 (m, 4H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(2-methylthiazole-4-yl)thiazole-4yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.27(d, J=5.4 Hz, 1H), 7.97 (s, 1H),6.99-7.21(m, 8H), 5.18-5.30 (m, 1H), 4.30-4.39 (m, 1H), 3.64 (s, 3H),3.20 (dd, J=14.1 and 6.6 Hz, 1H), 2.98-3.08(m, 2H), 2.84 (dd, J=14.1 and6.6 Hz, 1H), 2.78 (s, 3H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[(2-pyrazin-2-yl)thiazole-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 9.34 (s, 1H), 8.65 (s, 2H), 8.34 (d,J=8.1 Hz, 1H), 7.00-5.16 (m. 9H), 5.30 (q, J=7.2 Hz, 1H), 4.41 (t, J=7.2Hz, 1H), 3.65 (s, 3H), 3.23 (dd, J=13.8 and 6.9 Hz, 1H), 2.98-3.13 (m,2H), 2.85 (dd, J=13.8 and 6.9 Hz, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(6-methylpyridin-3-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.90 (s, 1H), 8.19-8.13 (m, 1H), 7.39-7.36 (d,1H, J=8.2 Hz), 7.07-6.88 (m, 9H), 6.79 (s, 1H), 5.17 (t, 1H, J=7.0 Hz),4.29 (t, 1H, J=7.4 Hz), 3.54 (s, 3H), 3.10-2.73 (m, 4H), 2.53 (s, 3H).

4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.96-7.93 (d, 2H, J=8.6 Hz), 7.83-7.80 (d, 2H,J=8.6 Hz), 7.44-7.34 (m, 5H), 7.29-7.27 (d, 2H, J=8.4 Hz), 7.14-7.11 (d,2H, J=8.4 Hz), 6.97 (s, 1H), 5.31 (t, 1H, J=6.8 Hz), 5.22-5.15 (m, 2H),4.55 (t, 1H, J=7.3 Hz), 3.84 (s, 3H), 3.20-2.96 (m, 4H).

4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl-amino)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.40-7.30 (m, 5H), 7.21-7.10 (m, 4H), 7.02 (s,1H), 5.37 (t, 1H, J=6.9 Hz), 5.01-4.98 (m, 2H), 4.51 (t, 1H, J=7.1 Hz),3.77 (s, 3H), 3.34-2.91 (m, 4H), 1.58 (s, 9H).

Category III of the present disclosure relates to compounds wherein R isa substituted or unsubstituted thiazol-2-yl unit having the formula:

one embodiment of which relates to inhibitors having the formula:

wherein R units are thiazol-2-yl units, that when substituted, aresubstituted with R² and R³ units. R and R^(5a) units are furtherdescribed in Table V.

TABLE V No. R R^(5a) E101 thiazol-2-yl (S)-benzyl E1024-methylthiazol-2-yl (S)-benzyl E103 4-ethylthiazol-2-yl (S)-benzyl E1044-propylthiazol-2-yl (S)-benzyl E105 4-iso-propylthiazol-2-yl (S)-benzylE106 4-cyclopropylthiazol-2-yl (S)-benzyl E107 4-butylthiazol-2-yl(S)-benzyl E108 4-tert-butylthiazol-2-yl (S)-benzyl E1094-cyclohexylthiazol-2-yl (S)-benzyl E1104-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl E1114-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl E1124-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl E1134-(methoxymethyl)thiazol-2-yl (S)-benzyl E114 4-(carboxylic acid ethylester)thiazol-2-yl (S)-benzyl E115 4,5-dimethylthiazol-2-yl (S)-benzylE116 4-methyl-5-ethylthiazol-2-yl (S)-benzyl E117 4-phenylthiazol-2-yl(S)-benzyl E118 4-(4-chlorophenyl)thiazol-2-yl (S)-benzyl E1194-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl E1204-methyl-5-phenylthiazol-2-yl (S)-benzyl E1214-(thiophen-2-yl)thiazol-2-yl (S)-benzyl E1224-(thiophen-3-yl)thiazol-2-yl (S)-benzyl E1234-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzyl E1245,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl E1254,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl

The compounds encompassed within Category III of the present disclosurecan be prepared by the procedure outlined in Scheme IV and described inExample 5 herein below.

EXAMPLE 54-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamicacid (15)

Preparation of(S)-2-acetamido-N-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)-ethyl]-3-phenylpropanamide(14): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.343 g, 0.957 mmol), N-acetyl-L-phenylalanine (0.218 g),1-hydroxybenzotriazole (HOBt) (0.161 g), diisopropyl-ethylamine (0.26g), in DMF (10 mL) at 0°, is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.201 g). Themixture is stirred at 0° C. for 30 minutes then at room temperatureovernight. The reaction mixture is diluted with water and extracted withEtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5%aqueous NaHCO₃, water and brine, and dried over Na₂SO₄. The solvent isremoved in vacuo to afford 0.313 g (70% yield) of the desired productwhich is used without further purification. LC/MS ESI+467 (M+1).

Preparation of4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (15):(S)-2-Acetamido-N-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-3-phenylpropanamide,14, (0.313 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 2 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.320 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH (30 mL) is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.215 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD) δ 7.23-6.98 (m, 10H), 5.37 (t, 1H), 4.64 (t, 1H,J=6.3 Hz), 3.26-2.74 (m, 6H), 1.91 (s, 3H), 1.29 (t, 3H, J=7.5 Hz).

The following are further non-limiting examples of compounds encompassedwithin

Category III of the present disclosure.

4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.22-7.17 (m, 5H), 7.06 (dd, J=14.1,8.4 Hz, 4H), 6.97 (d, J=0.9 Hz, 1H), 5.39 (dd, J=8.4, 6.0 Hz, 1H), 4.65(t, J=7.2 Hz, 1H), 3.33-3.26 (m, 1H), 3.13-3.00 (m, 2H), 2.80 (dd,J=13.5, 8.7 Hz, 1H), 1.91 (s, 3H), 1.36 (s, 9H).

4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.58 (d, J=8.1 Hz, 1H), 7.83-7.82 (m,1H), 7.57-7.46 (m, 3H), 7.28-6.93 (m, 11H), 5.54-5.43 (m, 1H), 4.69-4.55(m, 2H), 3.41-3.33 (m, 1H), 3.14-3.06 (3H), 2.86-2.79 (m, 1H), 1.93 (s,3H).

The first aspect of Category IV of the present disclosure relates tocompounds wherein R is a substituted or unsubstituted thiazol-2-yl unithaving the formula:

one embodiment of which relates to inhibitors having the formula:

wherein R units and Ry^(a) units further described in Table VI.

TABLE VI No. R R^(5a) F126 thiazol-2-yl hydrogen F1274-methylthiazol-2-yl hydrogen F128 4-ethylthiazol-2-yl hydrogen F1294-propylthiazol-2-yl hydrogen F130 4-iso-propylthiazol-2-yl hydrogenF131 4-cyclopropylthiazol-2-yl hydrogen F132 4-butylthiazol-2-ylhydrogen F133 4-tert-butylthiazol-2-yl hydrogen F1344-cyclohexylthiazol-2-yl hydrogen F135 4,5-dimethylthiazol-2-yl hydrogenF136 4-methyl-5-ethylthiazol-2-yl hydrogen F137 4-phenylthiazol-2-ylhydrogen F138 thiazol-2-yl (S)-iso-propyl F139 4-methylthiazol-2-yl(S)-iso-propyl F140 4-ethylthiazol-2-yl (S)-iso-propyl F1414-propylthiazol-2-yl (S)-iso-propyl F142 4-iso-propylthiazol-2-yl(S)-iso-propyl F143 4-cyclopropylthiazol-2-yl (S)-iso-propyl F1444-butylthiazol-2-yl (S)-iso-propyl F145 4-tert-butylthiazol-2-yl(S)-iso-propyl F146 4-cyclohexylthiazol-2-yl (S)-iso-propyl F1474,5-dimethylthiazol-2-yl (S)-iso-propyl F1484-methyl-5-ethylthiazol-2-yl (S)-iso-propyl F149 4-phenylthiazol-2-yl(S)-iso-propyl F150 4-(thiophen-2-yl)thiazol-2-yl (S)-iso-propyl

The compounds encompassed within Category IV of the present disclosurecan be prepared by the procedure outlined in Scheme V and described inExample 6 herein below.

EXAMPLE 64-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (17)

Preparation of tert-butyl(S)-1-[(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino]-3-methyl-1-oxobutan-2-ylcarbamate(16): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.200 g, 0.558 mmol),(S)-(2-tert-butoxycarbonylamino)-3-methylbutyric acid (0.133 g) and1-hydroxybenzo-triazole (HOBt) (0.094 g) in DMF (5 mL) at 0°, is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.118 g) followedby diisopropylamine (0.151 g). The mixture is stirred at 0° C. for 30minutes then at room temperature overnight. The reaction mixture isdiluted with water and extracted with EtOAc. The combined organic phaseis washed with 1 N aqueous HCl, 5% aqueous NaHCO₃, water and brine, anddried over Na₂SO₄. The solvent is removed in vacuo to afford 0.219 g(82% yield) of the desired product which is used without furtherpurification. LC/MS ESI+477 (M+1).

Preparation of4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (17): tert-Butyl(S)-1-[(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino]-3-methyl-1-oxobutan-2-ylcarbamate,16, (0.219 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 2 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (5 mL) and treated with SO₃-pyridine(0.146 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH (30 mL) is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.148 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD) δ 7.08 (s, 4H), 7.02 (s, 1H), 5.43 (s, 1H), 3.85(s, 1H), 3.28-2.77 (m, 4H), 1.94 (hep, 1H), 1.46 (s, 9H), 1.29 (s, 3H,J=7.3 Hz), 0.83 (d, 6H).

The following are further non-limiting examples of the second aspect ofCategory IV of the present disclosure.

(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}phenyl-sulfamicacid: ¹H NMR (CD₃OD) δ 7.09-6.91 (m, 5H), 5.30 (t, 1H, J=8.4 Hz),3.60-2.64 (m, 6H), 1.34 (s, 9H), 1.16 (t, 3H, J=7.5 Hz).

4-{(S)-2[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.19-7.00 (m, 5H), 5.50-5.40 (m, 1H), 4.13-4.06(m, 1H), 3.32 (1H, A of ABX, J=7.5, 18 Hz), 3.12 (1H, B of ABX, J=8.1,13.8 Hz), 2.79 (q, 2H, J=7.8, 14.7 Hz), 1.70-1.55 (m, 1H), 1.46 (s, 9H),1.33 (t, 3H, J=2.7 Hz), 0.92 (q, 6H, J=6, 10.8 Hz).

4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.06 (d, 1H, J=8.4 Hz), 7.61-7.58 (m, 1H), 7.57(s, 1H), 7.15 (t, 1H, J=0.6 Hz), 7.09-6.98 (m, 6H), 5.30-5.20 (m, 1H),4.10-4.00 (m, 1H), 3.19-3.13 (m, 2H), 1.63-1.55 (m, 2H), 1.48-1.33 (m,10H), 0.95-0.89 (m, 6H).

(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.09-6.91 (m, 5H), 5.30 (t, 1H, J=8.4 Hz),3.60-2.64 (m, 6H), 1.34 (s, 9H), 1.16 (t, 3H, J=7.5 Hz).

A further embodiment of Category IV relates to inhibitors having theformula:

wherein R units and R^(5a) units further described in Table VII.

TABLE VII No. R R^(5a) G151 thiazol-2-yl hydrogen G1524-methylthiazol-2-yl hydrogen G153 4-ethylthiazol-2-yl hydrogen G1544-propylthiazol-2-yl hydrogen G155 4-iso-propylthiazol-2-yl hydrogenG156 4-cyclopropylthiazol-2-yl hydrogen G157 4-butylthiazol-2-ylhydrogen G158 4-tert-butylthiazol-2-yl hydrogen G1594-cyclohexylthiazol-2-yl hydrogen G160 4,5-dimethylthiazol-2-yl hydrogenG161 4-methyl-5-ethylthiazol-2-yl hydrogen G162 4-phenylthiazol-2-ylhydrogen G163 thiazol-2-yl (S)-iso-propyl G164 4-methylthiazol-2-yl(S)-iso-propyl G165 4-ethylthiazol-2-yl (S)-iso-propyl G1664-propylthiazol-2-yl (S)-iso-propyl G167 4-iso-propylthiazol-2-yl(S)-iso-propyl G168 4-cyclopropylthiazol-2-yl (S)-iso-propyl G1694-butylthiazol-2-yl (S)-iso-propyl G170 4-tert-butylthiazol-2-yl(S)-iso-propyl G171 4-cyclohexythiazol-2-yl (S)-iso-propyl G1724,5-dimethylthiazol-2-yl (S)-iso-propyl G1734-methyl-5-ethylthiazol-2-yl (S)-iso-propyl G174 4-phenylthiazol-2-yl(S)-iso-propyl G175 4-(thiophen-2-yl)thiazol-2-yl (S)-iso-propyl

The compounds encompassed within this embodiment of Category IV can bemade according to the procedure outlined in Scheme V and described inExample 6 by substituting the corresponding methylcarbamate for theBoc-protected reagent. The following are non-limiting examples of thisembodiment.

4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-4-methylpentan-amido]ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.12-7.03 (m, 5H), 6.84 (d, 1H, J=8.4 Hz), 5.40(t, 1H, J=5.7 Hz), 4.16 (t, 1H, J=6.3 Hz), 3.69 (s, 3H), 3.61-3.55 (m,1H), 3.29-3.27 (m, 1H), 3.14-3.07 (m, 1H), 2.81 (q, 2H, J=3.9, 11.2 Hz),1.66-1.59 (m, 1H), 1.48-1.43 (m, 2H), 1.31 (t, 3H, J=4.5 Hz), 0.96-0.90(m, 6H).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonyeacetamido]ethyl}-phenylsulfamic acid: ¹H NMR (CD₃OD) δ 7.12-7.07 (m, 4H), 7.03 (s, 1H),5.42 (t, 1H, J=5.7 Hz), 3.83-3.68 (q, 2H, J=11.4 Hz), 3.68 (s, 3H),3.34-3.04 (m, 2H), 2.83-2.76 (q, 2H, J=7.8 Hz), 1.31 (t, 3H, J=7.5 Hz).

4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-methylbutanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.56 (d, 1H, J=7.8 Hz), 7.09 (s, 4H), 7.03 (s,1H), 5.26-5.20 (m, 1H), 3.90 (d, 1H, J=7.8 Hz), 3.70 (s, 3H), 3.30 (1H,A of ABX, obscured by solvent), 3.08 (1H, B of ABX, J=9.9, 9 Hz), 2.79(q, 2H, J=11.1, 7.2 Hz), 2.05-1.97 (m, 1H), 1.31 (t, 3H, J=7.5 Hz), 0.88(s, 3H), 0.85 (s, 3H), 0.79-0.75 (m, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.22 (d, 1H, J=9 Hz), 7.62-7.57 (m, H), 7.15 (t,1H, J=0.6 Hz), 7.10-6.97 (m, 4H), 5.30-5.20 (m, 1H), 4.16-4.11 (m, 1H),3.67 (s, 2H), 3.22 (1H, A of ABX, J=6.9, 13.5 Hz), 3.11 (1H, B of ABX,J=7.8, 13.6 Hz), 1.65-1.58 (m, 1H), 1.50-1.45 (m, 2H), 0.95-0.88 (m,6H).

Category IV of the present disclosure relates to compounds having theformula:

wherein R is a substituted or unsubstituted thiophen-2-yl orthiophen-4-yl unit and non-limiting examples of R° are further describedin Table VIII.

TABLE VIII No. R R⁸ H176 thiazol-2-yl —OC(CH₃)₃ H1774-methylthiazol-2-yl —OC(CH₃)₃ H178 4-ethylthiazol-2-yl —OC(CH₃)₃ H1794-cyclopropylthiazol-2-yl —OC(CH₃)₃ H180 4-tert-butylthiazol-2-yl—OC(CH₃)₃ H181 4-cyclohexylthiazol-2-yl —OC(CH₃)₃ H1824-(2,2,2-trifluoroethyl)thiazol-2-yl —OC(CH₃)₃ H1834-(3,3,3-trifluoropropyl)thiazol-2-yl —OC(CH₃)₃ H1844-(2,2-difluorocyclopropyl)thiazol-2-yl —OC(CH₃)₃ H1854,5-dimethylthiazol-2-yl —OC(CH₃)₃ H186 4-methyl-5-ethylthiazol-2-yl—OC(CH₃)₃ H187 4-phenylthiazol-2-yl —OC(CH₃)₃ H1884-(4-chlorophenyl)thiazol-2-yl —OC(CH₃)₃ H1894-(3,4-dimethylphenyl)thiazol-2-yl —OC(CH₃)₃ H1904-methyl-5-phenylthiazol-2-yl —OC(CH₃)₃ H1914-(thiophen-2-yl)thiazol-2-yl —OC(CH₃)₃ H192 thiazol-4-yl —OC(CH₃)₃ H1934-methylthiazol-4-yl —OC(CH₃)₃ H194 4-ethylthiazol-4-yl —OC(CH₃)₃ H1954-cyclopropylthiazol-4-yl —OC(CH₃)₃ H196 4-tert-butylthiazol-4-yl—OC(CH₃)₃ H197 4-cyclohexylthiazol-4-yl —OC(CH₃)₃ H1984-(2,2,2-trifluoroethyl)thiazol-4-yl —OC(CH₃)₃ H1994-(3,3,3-trifluoropropyl)thiazol-4-yl —OC(CH₃)₃ H2004-(2,2-difluorocyclopropyl)thiazol-4-yl —OC(CH₃)₃ H2014,5-dimethylthiazol-4-yl —OC(CH₃)₃ H202 4-methyl-5-ethylthiazol-4-yl—OC(CH₃)₃ H203 4-phenylthiazol-4-yl —OC(CH₃)₃ H2044-(4-chlorophenyl)thiazol-4-yl —OC(CH₃)₃ H2054-(3,4-dimethylphenyl)thiazol-4-yl —OC(CH₃)₃ H2064-methyl-5-phenylthiazol-4-yl —OC(CH₃)₃ H2074-(thiophen-2-yl)thiazol-4-yl —OC(CH₃)₃ H208 thiazol-2-yl —OCH₃ H2094-methylthiazol-2-yl —OCH₃ H210 4-ethylthiazol-2-yl —OCH₃ H2114-cyclopropylthiazol-2-yl —OCH₃ H212 4-tert-butylthiazol-2-yl —OCH₃ H2134-cyclohexylthiazol-2-yl —OCH₃ H214 4-(2,2,2-trifluoroethyl)thiazol-2-yl—OCH₃ H215 4-(3,3,3-trifluoropropyl)thiazol-2-yl —OCH₃ H2164-(2,2-difluorocyclopropyl)thiazol-2-yl —OCH₃ H2174,5-dimethylthiazol-2-yl —OCH₃ H218 4-methyl-5-ethylthiazol-2-yl —OCH₃H219 4-phenylthiazol-2-yl —OCH₃ H220 4-(4-chlorophenyl)thiazol-2-yl—OCH₃ H221 4-(3,4-dimethylphenyl)thiazol-2-yl —OCH₃ H2224-methyl-5-phenylthiazol-2-yl —OCH₃ H223 4-(thiophen-2-yl)thiazol-2-yl—OCH₃ H224 thiazol-4-yl —OCH₃ H225 4-methylthiazol-4-yl —OCH₃ H2264-ethylthiazol-4-yl —OCH₃ H227 4-cyclopropylthiazol-4-yl —OCH₃ H2284-tert-butylthiazol-4-yl —OCH₃ H229 4-cyclohexylthiazol-4-yl —OCH₃ H2304-(2,2,2-trifluoroethyl)thiazol-4-yl —OCH₃ H2314-(3,3,3-trifluoropropyl)thiazol-4-yl —OCH₃ H2324-(2,2-difluorocyclopropyl)thiazol-4-yl —OCH₃ H2334,5-dimethylthiazol-4-yl —OCH₃ H234 4-methyl-5-ethylthiazol-4-yl —OCH₃H235 4-phenylthiazol-4-yl —OCH₃ H236 4-(4-chlorophenyl)thiazol-4-yl—OCH₃ H237 4-(3,4-dimethylphenyl)thiazol-4-yl —OCH₃ H2384-methyl-5-phenylthiazol-4-yl —OCH₃ H239 4-(thiophen-2-yl)thiazol-4-yl—OCH₃ H240 thiazol-2-yl —CH₃ H241 4-methylthiazol-2-yl —CH₃ H2424-ethylthiazol-2-yl —CH₃ H243 4-cyclopropylthiazol-2-yl —CH₃ H2444-tert-butylthiazol-2-yl —CH₃ H245 4-cyclohexylthiazol-2-yl —CH₃ H2464-(2,2,2-trifluoroethyl)thiazol-2-yl —CH₃ H2474-(3,3,3-trifluoropropyl)thiazol-2-yl —CH₃ H2484-(2,2-difluorocyclopropyl)thiazol-2-yl —CH₃ H2494,5-dimethylthiazol-2-yl —CH₃ H250 4-methyl-5-ethylthiazol-2-yl —CH₃H251 4-phenylthiazol-2-yl —CH₃ H252 4-(4-chlorophenyl)thiazol-2-yl —CH₃H253 4-(3,4-dimethylphenyl)thiazol-2-yl —CH₃ H2544-methyl-5-phenylthiazol-2-yl —CH₃ H255 4-(thiophen-2-yl)thiazol-2-yl—CH₃ H256 thiazol-4-yl —CH₃ H257 4-methylthiazol-4-yl —CH₃ H2584-ethylthiazol-4-yl —CH₃ H259 4-cyclopropylthiazol-4-yl —CH₃ H2604-tert-butylthiazol-4-yl —CH₃ H261 4-cyclohexylthiazol-4-yl —CH₃ H2624-(2,2,2-trifluoroethyl)thiazol-4-yl —CH₃ H2634-(3,3,3-trifluoropropyl)thiazol-4-yl —CH₃ H2644-(2,2-difluorocyclopropyl)thiazol-4-yl —CH₃ H2654,5-dimethylthiazol-4-yl —CH₃ H266 4-methyl-5-ethylthiazol-4-yl —CH₃H267 4-phenylthiazol-4-yl —CH₃ H268 4-(4-chlorophenyl)thiazol-4-yl —CH₃H269 4-(3,4-dimethylphenyl)thiazol-4-yl —CH₃ H2704-methyl-5-phenylthiazol-4-yl —CH₃ H271 4-(thiophen-2-yl)thiazol-4-yl—CH₃

The compounds encompassed within Category IV of the present disclosurecan be prepared by the procedure outlined in Scheme VI and described inExample 7 herein below.

EXAMPLE 7[1-(S)-(Phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic acidtert-butyl ester (19)

Preparation of[2-(4-nitrophenyl)-1-(S)-(4-phenylthiazol-2-yl)ethyl]-carbamic acidtert-butyl ester (18): A mixture of[2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid tert-butylester, 2, (0.343 g, 1.05 mmol), 2-bromoacetophenone (0.231 g, 1.15mmol), in CH₃CN (5 mL) is refluxed 1.5 hour. The solvent is removedunder reduced pressure and the residue re-dissolved in CH₂Cl₂ thenpyridine (0.24 mL, 3.0 mmol) and Boc₂O (0.24 mL, 1.1 mmol) are added.The reaction is stirred for 2 hours and diethyl ether is added to thesolution and the precipitate which forms is removed by filtration. Theorganic layer is dried (Na₂SO₄), filtered, and concentrated to a residuewhich is purified over silica to afford 0.176 g (39%) of the desiredproduct ESI+MS 426 (M+1).

Preparation of[1-(S)-(phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic acidtert-butyl ester (19):[2-(4-nitrophenyl)-1-(S)-(4-phenylthiazol-2-yl)ethyl]-carbamic acidtert-butyl ester, 18, (0.176 g, 0.41 mmol) is dissolved in MeOH (4 mL).A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 12 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (12 mL) and treatedwith SO₃-pyridine (0.195 g, 1.23 mmol). The reaction is stirred at roomtemperature for 5 minutes after which a 7% solution of NH₄OH (10 mL) isadded. The mixture is then concentrated and the resulting residue ispurified by reverse phase chromatography to afford 0.080 g of thedesired product as the ammonium salt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.93(d, J=6.0 Hz, 2H), 7.68 (s, 1H), 7.46-7.42 (m, 3H), 7.37-7.32 (m, 1H),7.14-7.18 (m, 3H), 5.13-5.18 (m, 1H), 3.40 (dd, J=4.5 and 15.0 Hz, 1H),3.04 (dd, J=9.6 and 14.1 Hz, 1H), 1.43 (s, 9H).

The following are further non-limiting examples of Category IV of thepresent disclosure.

(S)-4-(2-(4-Methylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid:¹H NMR(CD₃OD) δ 7.31 (s, 4H), 7.20 (s, 1H), 5.61-5.56 (m, 1H), 3.57-3.22(m, 2H), 2.62 (s, 3H), 1.31 (s, 3H).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid: ¹HNMR (300 MHz, MeOH-d₄) δ 7.92 (d, J=8.1 Hz, 1H), 7.12-7.14 (m, 4H), 7.03(s, 1H), 5.38-5.46 (m, 1H), 3.3-3.4 (m, 1H), 3.08 (dd, J=10.2 and 13.8Hz, 1H), 2.79 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.13 (s, 9H).

(S)-4-(2-(4-(Hydroxymethyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.92 (d, J=8.1 Hz, 1H), 7.24 (s, 1H),7.08 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.29-5.37 (m, 1H), 4.55(s, 2H), 3.30 (dd, J=4.8 and 13.5 Hz, 1H), 2.99 (dd, J=10.5 and 13.5 Hz,1H), 0.93 (s, 9H).

(S)-4-(2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.30 (s, 1H), 8.04 (d, J=8.1 Hz, 1H),7.13 (s, 4H), 5.41-5.49 (m, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.43 (dd, J=5.1and 13.8 Hz, 1H), 3.14 (dd, J=5.7 and 9.9 Hz, 1H), 1.42 (t, J=7.2 Hz,3H), 1.14 (s, 9H).

(S)-4-(2-(4-Phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid:¹H NMR (300 MHz, MeOH-d₄) δ 7.94-8.01 (m, 3H), 7.70 (s, 1H), 7.42-7.47(m, 2H), 7.32-7.47 (m, 1H), 7.13-7.20 (m, 3H), 5.48-5.55 (m, 1H), 3.50(dd, J=5.1 and 14.1 Hz, 1H), 3.18 (dd, J=10.2 and 14.1 Hz, 1H), 1.17 (s,9H).

4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.96-7.93 (d, 1H, J=8.1 Hz), 7.69 (s, 1H),7.51-7.49 (d, 2H, J=7.9 Hz), 7.33 (t, 1H, J=8.0 Hz), 7.14 (s, 4H),6.92-6.90 (d, 1H, J=7.8 Hz), 5.50 (t, 1H, J=5.1 Hz), 3.87 (s, 3H),3.50-3.13 (m, 2H), 1.15 (s, 9H).

4-((S)-2-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.11-8.09 (d, 1H, J=7.8 Hz), 7.96-7.93 (d, 1H,J=8.4 Hz), 7.74 (s, 1H), 7.18-7.16 (m, 4H), 6.67-6.64 (d, 2H, J=9.0 Hz),5.55-5.47 (m, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.52-3.13 (m, 2H), 1.17(s, 9H).

(S)-4-(2-(4-Benzylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid:¹H NMR (CD₃OD) δ 7.85 (d, 1H, J=8.4 Hz), 7.38-7.20 (m, 4H), 7.11-7.02(m, 1H), 7.00 (s, 1H), 5.42-5.37 (m, 1H), 4.13 (s, 2H), 3.13-3.08 (m,2H), 1.13 (s, 9H).

(S)-4-(2-Pivalamido-2-(4-(thiophen-2-ylmethyl)thiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.88-7.85 (d, 1H), 7.38-7.35 (m, 1H), 7.10-7.01(m, 4H), 7.02 (s, 1H), 5.45-5.38 (m, 1H), 4.13 (s, 2H), 3.13-3.05 (m,2H), 1.13 (2, 9H).

(S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.85 (d, 1H, J=8.4 Hz), 7.25-7.20 (m, 1H),7.11-7.02 (m, 4H), 7.01 (s, 1H), 6.90-6.79 (m, 2H), 5.45-5.40 (m, 1H),4.09 (s, 2H), 3.79 (s, 3H), 3.12-3.08 (m, 2H), 1.10 (s, 9H).

4-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-pivalamidoethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.53 (s, 1H), 7.45 (s, 1H), 7.42-7.40 (d, 1H,J=8.4 Hz), 7.19-7.15 (m, 4H), 6.91-6.88 (d, 2H, J=8.4 Hz), 5.51-5.46 (m,1H), 4.30 (s, 4H), 3.51-3.12 (m, 2H), 1.16 (s, 9H).

(S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.63-7.60 (d, 2H, J=7.1 Hz), 7.49-7.35 (m, 3H),7.14 (s, 4H), 5.43-5.38 (m, 1H), 3.42-3.09 (m, 2H), 2.49 (s, 3H), 1.14(s, 9H).

(S)-4-(2-(4-(Biphen-4-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.04-8.01 (m, 2H), 7.72-7.66 (m, 5H), 7.48-7.35(m, 3H), 7.15 (s, 4H), 5.50 (t, 1H, J=5.0 Hz), 3.57-3.15 (d, 2H), 1.16(s, 9H).

(S)-4-(2-tert-Butoxycarbonyl-2-(2-methylthaizol-4-yl)-phenylsulfamicacid ¹H NMR (300 MHz, D₂O) δ 6.99-7.002(m, 4H), 6.82 (s, 1H), 2.26 (dd,J=13.8 and 7.2 Hz, 1H), 2.76 (dd, J=13.8 and 7.2 Hz, 1H), 2.48 (s, 3H),1.17 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-propylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.18-7.02 (m, 5H), 5.06-5.03(m, 1H), 3.26 (dd, J=13.8, 4.8 Hz, 1H), 2.95 (dd, J=13.8, 9.3 Hz, 1H),2.74 (dd, J=15.0, 7.2 Hz, 2H), 1.81-1.71 (m, 2H), 1.40 (s, 7H), 1.33(bs, 2H), 0.988 (t, J=7.5 Hz 3H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-tert-butylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.12 (s, 4H), 7.01 (s, 1H),5.11-5.06 (m, 1H), 3.32-3.25 (m, 1H), 2.96 (m, 1H), 1.42 (s, 8H), 1.38(s, 9H), 1.32 (s, 1H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.36 (s, 1H), 7.14-7.05 (m,4H), 5.06 (dd, J=9.0, 5.1 Hz, 1H), 4.55 (s, 2H), 3.42 (s, 3H), 3.31-3.24(m, 1H), 2.97 (dd, J=13.8, 9.9 Hz, 1H), 1.47-1.31 (m, 9H).

(S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-hydroxymethyl)thiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.22-7.25 (m, 1H), 7.09-7.15 (m, 4H),5.00-5.09 (m, 1H), 4.32-4.35 (m, 1H), 3.87 (t, J=6.6 Hz, 2H), 3.23-3.29(m, 1H), 3.09-3.18 (m, 1H), 2.98 (t, J=6.6 Hz, 2H), 1.41 (s, 9H).

(S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-ethoxy-2-oxoethyl)-thiazole-2-yl)-ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.29 (s, 1H), 7.09-7.16 (m, 4H),5.04-5.09 (m, 1H), 4.20 (q, J=6.9 Hz, 2H), 3.84 (s, 2H), 3.30 (dd, J=4.8and 14.1 HZ, 1H), 2.97 (dd, J=9.6 Hz and 13.8 Hz, 1H), 1.41 (s, 9H),1.29 (t, J=7.2 Hz, 3H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(2-methoxy-2-oxoethyl)thiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.31 (s, 1H), 7.01-7.16 (m, 4H),5.04-5.09 (m, 1H), 4.01 (s, 2H), 3.78 (s, 2H), 3.74 (s, 3H), 3.29 (dd,J=5.1 and 13.8 Hz, 1H), 2.99 (dd, J=9.3 and 13.8 Hz, 1H), 1.41 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(5-phenylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.98 (s, 1H), 7.62 (d, J=7.2Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s, 4H), 5.09 (bs, 1H), 3.07-2.99 (m,2H), 1.43 (s, 9H).

4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)ethyl)phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 8.28 (s, 1H), 8.22-8.19 (m,1H),7.89 (s, 1H), 7.65 (d, J=5.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 1H), 7.15(s, 4H), 5.17-5.14 (m, 1H), 3.43-3.32 (m, 1H), 3.05 (dd, J=14.1, 9.6 Hz,1H), 1.42 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-phenylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.98 (s, 1H), 7.94 (d, J=7.2Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s, 4H), 5.09 (bs, 1H), 3.07-2.99 (m,2H), 1.43 (s, 9H).

(S,S)-2-(2-{2-[2-tert-Butoxycarbonylamino-2-(4-sulfoaminophenyl)ethyl]thiazol-4-yl}acetylamido)-3-phenylpropionic acidmethyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 6.85-6.94 (m, 9H), 6.64 (s,1H), 4.83 (s, 1H), 4.54-4.58 (m, 1H), 3.49 (s, 3H), 3.39 (s, 2H),2.80-2.97 (m, 1H), 2.64-2.78 (m, 1H), 1.12 (s, 9H).

(S)-[1-{1-Oxo-4-[2-(1-phenyl-1H-tetrazol-5-sulfonyl)ethyl]-1H-1λ⁴-thiazol-2-yl}-2-(4-sulfamino-phenyl)-ethyl]-carbamicacid tert-butyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 7.22-7.75 (m, 2H),7.62-7.69 (m, 2H), 7.55 (s, 1H), 7.10-7.20 (m, 5H), 5.25 (m, 1H),4.27-4.36 (m, 1H), 4.11-4.21 (m, 1H), 3.33-3.44 (m, 4H), 2.84-2.90 (m,1H), 1.33 (s, 9H).

4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(thiophen-3-yl)thiazol-2-yl)ethyl)phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.84 (dd, J=3.0, 1.5 Hz, 1H),7.57-7.55 (m, 2H), 7.47 (dd, J=4.8, 3.0 Hz, 1H), 7.15(s, 4H), 5.15-5.10(m, 1H), 3.39-3.34 (m, 1H), 3.01 (dd, J=14.1, 9.6 Hz, 1H), 1.42 (s, 8H),1.32 (s, 1H).

(S)-4-(2-(Benzo[d]thiazol-2-ylamino)-2-(tert-butoxycarbonyl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.86-7.82 (m, 2H), 7.42 (t, 2H, J=7.1 Hz), 7.33(t, 1H, J=8.2 Hz), 7.02 (s, 4H), 5.10-5.05 (m, 1H), 2.99-2.91 (m, 2H),1.29 (s, 9H).

(S)-4-(2-tert-Butoxycarbonylamino)-2-(2-methylthiazol-4-yl)-phenylsulfamicacid ¹H NMR (300 MHz, D₂O) δ 6.99-7.002(m, 4H), 6.82 (s, 1H), 2.26 (dd,J=13.8 and 7.2 Hz, 1H), 2.76 (dd, J=13.8 and 7.2 Hz, 1H), 2.48 (s, 3H),1.17 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(2-(pivaloyloxy)thiazol-4-yl)ethyl)-phenylsulfamicacid: ¹H NMR (300 MHz, D₂O) δ 6.95 (s, 4H), 6.63 (s, 1H), 2.94 (dd,J=13.5 and 4.8 Hz, 1H), 2.75 (dd, J=13.5 and 4.8 Hz, 1H), 1.16 (s, 9H),1.13 (s, 9H).

The first aspect of Category V of the present disclosure relates to2-(thiazol-2-yl) compounds having the formula:

wherein R¹, R², R³, and L are further defined herein in Table IX below.

TABLE IX No. L R¹ R² R³ I272 —CH₂— phenyl —CH₃ —H I273 —CH₂—2-fluorophenyl —CH₃ —H I274 —CH₂— 3-fluorophenyl —CH₃ —H I275 —CH₂—4-fluorophenyl —CH₃ —H I276 —CH₂— 2,3-difluorophenyl —CH₃ —H I277 —CH₂—3,4-difluorophenyl —CH₃ —H I278 —CH₂— 3,5-difluorophenyl —CH₃ —H I279—CH₂— 2-chlorophenyl —CH₃ —H I280 —CH₂— 3-chlorophenyl —CH₃ —H I281—CH₂— 4-chlorophenyl —CH₃ —H I282 —CH₂— 2,3-dichlorophenyl —CH₃ —H I283—CH₂— 3,4-dichlorophenyl —CH₃ —H I284 —CH₂— 3,5-dichlorophenyl —CH₃ —HI285 —CH₂— 2-hydroxyphenyl —CH₃ —H I286 —CH₂— 3-hydroxyphenyl —CH₃ —HI287 —CH₂— 4-hydroxyphenyl —CH₃ —H I288 —CH₂— 2-methoxyphenyl —CH₃ —HI289 —CH₂— 3-methoxyphenyl —CH₃ —H I290 —CH₂— 4-methoxyphenyl —CH₃ —HI291 —CH₂— 2,3-dimethoxyphenyl —CH₃ —H I292 —CH₂— 3,4-dimethoxyphenyl—CH₃ —H I293 —CH₂— 3,5-dimethoxyphenyl —CH₃ —H I294 —CH₂— phenyl —CH₂CH₃—H I295 —CH₂— 2-fluorophenyl —CH₂CH₃ —H I296 —CH₂— 3-fluorophenyl—CH₂CH₃ —H I297 —CH₂— 4-fluorophenyl —CH₂CH₃ —H I298 —CH₂—2,3-difluorophenyl —CH₂CH₃ —H I299 —CH₂— 3,4-difluorophenyl —CH₂CH₃ —HI300 —CH₂— 3,5-difluorophenyl —CH₂CH₃ —H I301 —CH₂— 2-chlorophenyl—CH₂CH₃ —H I302 —CH₂— 3-chlorophenyl —CH₂CH₃ —H I303 —CH₂—4-chlorophenyl —CH₂CH₃ —H I304 —CH₂— 2,3-dichlorophenyl —CH₂CH₃ —H I305—CH₂— 3,4-dichlorophenyl —CH₂CH₃ —H I306 —CH₂— 3,5-dichlorophenyl—CH₂CH₃ —H I307 —CH₂— 2-hydroxyphenyl —CH₂CH₃ —H I308 —CH₂—3-hydroxyphenyl —CH₂CH₃ —H I309 —CH₂— 4-hydroxyphenyl —CH₂CH₃ —H I310—CH₂— 2-methoxyphenyl —CH₂CH₃ —H I311 —CH₂— 3-methoxyphenyl —CH₂CH₃ —HI312 —CH₂— 4-methoxyphenyl —CH₂CH₃ —H I313 —CH₂— 2,3-dimethoxyphenyl—CH₂CH₃ —H I314 —CH₂— 3,4-dimethoxyphenyl —CH₂CH₃ —H I315 —CH₂—3,5-dimethoxyphenyl —CH₂CH₃ —H I316 —CH₂CH₂— phenyl —CH₃ —H I317—CH₂CH₂— 2-fluorophenyl —CH₃ —H I318 —CH₂CH₂— 3-fluorophenyl —CH₃ —HI319 —CH₂CH₂— 4-fluorophenyl —CH₃ —H I320 —CH₂CH₂— 2,3-difluorophenyl—CH₃ —H I321 —CH₂CH₂— 3,4-difluorophenyl —CH₃ —H I322 —CH₂CH₂—3,5-difluorophenyl —CH₃ —H I323 —CH₂CH₂— 2-chlorophenyl —CH₃ —H I324—CH₂CH₂— 3-chlorophenyl —CH₃ —H I325 —CH₂CH₂— 4-chlorophenyl —CH₃ —HI326 —CH₂CH₂— 2,3-dichlorophenyl —CH₃ —H I327 —CH₂CH₂—3,4-dichlorophenyl —CH₃ —H I328 —CH₂CH₂— 3,5-dichlorophenyl —CH₃ —H I329—CH₂CH₂— 2-hydroxyphenyl —CH₃ —H I330 —CH₂CH₂— 3-hydroxyphenyl —CH₃ —HI331 —CH₂CH₂— 4-hydroxyphenyl —CH₃ —H I332 —CH₂CH₂— 2-methoxyphenyl —CH₃—H I333 —CH₂CH₂— 3-methoxyphenyl —CH₃ —H I334 —CH₂CH₂— 4-methoxyphenyl—CH₃ —H I335 —CH₂CH₂— 2,3-dimethoxyphenyl —CH₃ —H I336 —CH₂CH₂—3,4-dimethoxyphenyl —CH₃ —H I337 —CH₂CH₂— 3,5-dimethoxyphenyl —CH₃ —HI338 —CH₂CH₂— phenyl —CH₂CH₃ —H I339 —CH₂CH₂— 2-fluorophenyl —CH₂CH₃ —HI340 —CH₂CH₂— 3-fluorophenyl —CH₂CH₃ —H I341 —CH₂CH₂— 4-fluorophenyl—CH₂CH₃ —H I342 —CH₂CH₂— 2,3-difluorophenyl —CH₂CH₃ —H I343 —CH₂CH₂—3,4-difluorophenyl —CH₂CH₃ —H I344 —CH₂CH₂— 3,5-difluorophenyl —CH₂CH₃—H I345 —CH₂CH₂— 2-chlorophenyl —CH₂CH₃ —H I346 —CH₂CH₂— 3-chlorophenyl—CH₂CH₃ —H I347 —CH₂CH₂— 4-chlorophenyl —CH₂CH₃ —H I348 —CH₂CH₂—2,3-dichlorophenyl —CH₂CH₃ —H I349 —CH₂CH₂— 3,4-dichlorophenyl —CH₂CH₃—H I350 —CH₂CH₂— 3,5-dichlorophenyl —CH₂CH₃ —H I351 —CH₂CH₂—2-hydroxyphenyl —CH₂CH₃ —H I352 —CH₂CH₂— 3-hydroxyphenyl —CH₂CH₃ —H I353—CH₂CH₂— 4-hydroxyphenyl —CH₂CH₃ —H I354 —CH₂CH₂— 2-methoxyphenyl—CH₂CH₃ —H I355 —CH₂CH₂— 3-methoxyphenyl —CH₂CH₃ —H I356 —CH₂CH₂—4-methoxyphenyl —CH₂CH₃ —H I357 —CH₂CH₂— 2,3-dimethoxyphenyl —CH₂CH₃ —HI358 —CH₂CH₂— 3,4-dimethoxyphenyl —CH₂CH₃ —H I359 —CH₂CH₂—3,5-dimethoxyphenyl —CH₂CH₃ —H

The compounds encompassed within the first aspect of Category V of thepresent disclosure can be prepared by the procedure outlined in SchemeVII and described in Example 8 herein below.

EXAMPLE 8

{4-[2-(S)-(4-Ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]phenyl}sulfamicacid (21)

Preparation ofN-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide(20): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g, 1.4 mmol) and1-hydroxybenzotriazole (HOBt) (0.094 g, 0.70 mmol) in DMF (10 mL) at 0°,is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.268 g,1.4 mmol) followed by triethylamine (0.60 mL, 4.2 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford 0.260 g (60% yield) of the desired product which isused without further purification. ESI+MS 396 (M+1).

Preparation of{4-[2-(S)-(4-ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]-phenyl}sulfamicacid (21):N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide,20, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.177 g, 1.23). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH (10 mL) is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford 0.136 g of the desired product as theammonium salt. ¹H NMR (CD₃OD) δ 8.60 (d, 1H, J=8.1 Hz), 7.33-7.23 (m,3H), 7.16-7.00 (m, 6H), 5.44-5.41 (m, 1H), 3.28 (1H, A of ABX, obscuredby solvent), 3.03 (1H, B of ABX, J=14.1, 9.6 Hz), 2.80 (q, 2H, J=10.5,7.8 Hz) 1.31 (t, 3H, J=4.6 Hz).

The following are non-limiting examples of the first aspect of CategoryV of the present disclosure.

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.65(d, 1H, J=8.4 Hz), 7.29-7.15 (m, 1H),7.13-7.03 (m, 7H), 5.46-5.42 (m, 1H), 3.64-3.51 (m, 2H), 3.29 (1H), 3.04(1H, B of ABX, J=13.8, 9.6 Hz), 2.81 (q, 2H, J=15.6, 3.9 Hz), 1.31 (t,3H, J=7.8 Hz). ¹⁹F NMR (CD₃OD) δ 43.64.

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.74 (d, 1H, J=8.4 Hz), 7.32 (q, 1H, J=6.6, 14.2Hz), 7.10-6.91 (m, 8H), 5.47-5.40 (m, 1H), 3.53 (s, 2H), 3.30 (1H), 3.11(1H, B of ABX, J=9.6, 14.1 Hz), 2.80 (q, 2H, J=6.6, 15.1 Hz), 1.31 (t,3H, J=7.8 Hz). 19F NMR δ 47.42.

(S)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.16-7.05 (m, 5H), 6.85-6.80 (m, 1H), 5.48-5.43(m, 1H), 3.63 (s, 2H), 3.38 (1H, A of ABX, obscured by solvent), 3.03(1H), 2.80 (q, H, J=15.1, 7.8 Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.75 (d, 1H, J=7.8 Hz), 7.23-7.04 (m, 6H),6.88-6.84 (m, 1H), 5.44-5.40 (m, 1H), 3.49 (s, 2H), 3.34 (1H), 3.02 (1H,B of ABX, J=14.1, 9.9 Hz), 2.80 (q, 2H, J=15.1, 7.8 Hz), 1.31 (t, 1H,J=7.5 Hz). 19F NMR (CD3OD) δ 22.18, 19.45.

(S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.39-7.36 (m, 1H), 7.27-7.21 (m, 2H), 7.15-6.98(m, 5H), 5.49-5.44 (m, 1H), 3.69 (d, 2H, J=11.7 Hz), 3.32 (1H), 3.04(1H, B of ABX, J=9.3, 13.9 Hz), 2.80 (q, 2H, J=7.8, 15.3 Hz), 1.31 (t,3H, J=7.5 Hz).

(S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.33-7.23 (m, 3H), 7.13-7.03 (m, 5H), 5.43 (q,1H, J=5.1, 9.6 Hz), 3.51 (s, 2H), 3.29 (1H), 3.03 (1H, B of ABX, J=9.9,14.1 Hz), 2.80 (q, 2H, J=7.5, 15 Hz), 1.31 (t, 3H, J=7.8 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.16-7.08 (m, 3H), 7.03-7.00 (m, 3H), 6.70-6.63(m, 2H), 5.42-5.40 (m, 1H), 3.44 (s, 2H), 3.28 (1H, A of ABX, obscuredby solvent), 3.04 (B of ABX, J=14.1, 9.6 Hz), 2.89 (q, 2H, J=15, 7.5Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.00 (d, 1H, J=7.8 Hz), 7.26 (t, 1H, J=13.2 Hz),7.09-7.05 (m, 4H), 7.01 (s, 1H), 6.91-6.89 (m, 4H), 5.44-5.39 (m, 1H),3.71 (s, 3H), 3.52 (s, 2H), 3.26 (1H, A of ABX, J=14.1, 5.1 Hz), 3.06(1H B of ABX, J=13.8, 8.4 Hz), 2.80 (q, 2H, J=8.1, 15.6 Hz), 1.31 (t,3H, J=1.2 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)acetamido]ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.58 (d, 1H, J=8.1 Hz), 7.21 (t, 1H, J=7.8 Hz),7.12-7.02 (m, 4H), 6.81 (s, 2H), 6.72 (d, 1H, J=7.5 Hz), 5.45-5.40 (m,1H), 3.79 (s, 3H), 3.50 (s, 2H), 3.29 (1H, A of ABX, obscured bysolvent), 3.08 (1H, B of ABX, J=11.8, 5.1 Hz), 2.80 (q, 2H, J=15, 7.5Hz), 1.31 (t, 3H, J=6.6 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.56 (d, 1H, J=8.4 Hz), 7.25-6.98 (m, 9H),5.43-5.38 (m, 1H), 3.26 (1H, A of ABX, J=14.1, 9.6 Hz), 2.97 (1H, B ofABX, J=10.9, 3 Hz), 2.58-2.76 (m, 3H), 2.98 (q, 2H, J=13.8, 7.2 Hz),1.29 (t, 3H, J=8.7 Hz).

(S)-4-(2-(2-(3,4-Dimethoxyp henyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (CD₃OD) δ 7.12-7.03 (m,3H), 6.91 (d, 1H, J=8.4 Hz), 6.82 (s, 1H), 6.66 (d, 1H, J=2.1 Hz), 6.63(d, 1H, J=2.1 Hz), 5.43 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.45 (s,2H), 3.30 (1H), 3.03 (1H, B of ABX, J=14.1, 9.6 Hz), 2.79 (q, 2H,J=15.1, 7.2 Hz), 1.30 (t, 3H, J=7.2 Hz).

(S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.31 (d, 1H, J=7.8 Hz), 7.11-6.93 (m, 6H), 6.68(d, 1H, J=7.5 Hz), 5.49-5.40 (m, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 3.55(s, 2H), 3.26 (1H, A of ABX, obscured by solvent), 3.06 (1H, B of ABX,J=13.9, 9 Hz), 2.80 (q, 2H, J=14.8, 7.5 Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamicacid: ¹H NMR (CD3OD) δ 7.27-7.18 (m, 3H), 7.13-7.08 (m, 5H), 7.01 (s,1H), 5.39 (q, 1H, J=5.1, 9.4 Hz), 3.28 (1H, A of ABX, J=5.1, 14.1 Hz),2.97 (1H, B of ABX, J=9.3, 13.9 Hz), 2.88-2.76 (m, 4H), 2.50 (t, 2H,J=8.1 Hz), 1.31 (t, 3H, J=7.8 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.18-7.08 (m, 6H), 6.92 (d, 1H, J=8.1 Hz), 6.82(t, 1H, J=7.5 Hz), 5.40-5.35 (m, 1H), 3.25 (1H, A of ABX, J=15, 5.4 Hz),3.00 (1H, B of ABX, J=10.5, 7.5 Hz), 2.88-2.76 (m, 4H), 2.47 (q, 2H,J=9.1, 6 Hz), 1.31 (t, 3H, J=7.8 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.19-7.00 (m, 5H), 6.75 (s, 1H), 6.73 (s, 1H),5.42-5.37 (m, 1H), 3.76 (s, 3H), 3.25 (1H, A of ABX, J=13.9, 5.4 Hz),2.98 (1H, B of ABX, J=14.1, 9.6 Hz), 2.86-2.75 (m, 4H), 2.48 (q, 2H,J=11.7, 1.2 Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.13-6.99 (m, 7H), 6.82-6.78 (m, 2H), 5.42-5.37(m, 1H), 3.33 (s, 3H), 3.23 (1H), 2.97 (1H, B of ABX, J=13.3, 11.4 Hz),2.83-2.75 (m, 4H), 2.49 (q, 2H, J=6.4, 3.3 Hz), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.14 (s, 4H), 7.08 (s, 1H), 5.56-5.51 (m, 1H),4.34 (d, 2H, J=16.2 Hz), 3.88 (d, 2H, J=17.6 Hz), 3.59-3.40 (m, 3H),3.26-3.14 (m, 3H), 2.98 (1H, B of ABX, J=10.8, 13.9 Hz), 2.82 (q, 2H,J=6.9, 15 Hz), 1.32 (t, 3H, J=7.5 Hz), 1.21 (t, 3H, J=7.2 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.13 (s, 1H), 7.06-7.02 (m, 4H), 6.95 (s, 1H),5.42-5.31 (m, 1H), 4.43-4.18 (dd, 2H, J=16.5 Hz), 3.24-2.93 (m, 2H),2.74-2.69 (q, 2H, J=7.3 Hz), 1.79 (s, 3H), 1.22 (t, 3H, J=7.5 Hz).

(S)-4-[2-(benzo[d][1,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.25 (d, 1H, J=6.5 Hz), 7.13 (s, 1H), 7.06 (d,2H, J=8.5 Hz), 7.00 (d, 2H, J=8.5 Hz), 6.91 (s, 1H), 6.76 (d, 1H, J=8.1Hz), 5.90 (s, 2H), 5.48 (q, 1H, J=5.0 Hz), 3.32-3.24 (m, 2H), 3.07-2.99(m, 2H), 2.72 (q, 2H, J=7.5 Hz), 1.21 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.10-7.01 (m, 5H), 5.41 (t, 1H, J=6.9 Hz), 3.58(s, 2H), 3.33-3.01 (m, 2H), 2.82-2.75 (q, 2H, J=7.5 Hz), 2.59 (s, 3H),2.23 (s, 3H), 1.30 (t, 3H, J=7 .5 Hz).

(S)-4-{2-[2-(2,4-Dimethylthiazol-5-yl)acetamido]-2-(4-methylthiazol-2-yl)ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.71-8.68 (d, 1H, J=8.4 Hz), 7.10-7.03 (m, 4H),7.01 (s, 1H), 5.41 (m, 1H), 3.59 (s, 1H), 3.34-2.96 (m, 2H), 2.59 (s,3H), 2.40 (s, 3H), 2.23 (s, 3H).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[3-(thiazol-2-yl)propanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD):(S)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.10-7.01 (m, 5H), 5.41 (t, 1H, J=6.9 Hz), 3.58(s, 2H), 3.33-3.01 (m, 2H), 2.82-2.75 (q, 2H, J=7.5 Hz), 2.59 (s, 3H),2.23 (s, 3H), 1.30 (t, 3H, J=7.5 Hz).

7.67-7.65 (m, 1H), 7.49-7.47 (m, 1H), 7.14-7.08 (m, 4H), 7.04 (s, 1H),5.46-5.41 (q, 1H, J=5.1 Hz), 3.58 (s, 2H), 3.30-3.25 (m, 3H), 3.02-2.67(m, 5H), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(4-ethylthiazol-2-yl)acetamido]ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.04-6.91 (m, 6H), 5.32 (t, 1H, J=5.4 Hz),3.25-2.90 (m, 2H), 2.71-2.61 (m, 4H) 1.93 (s, 2H) 1.22-1.14 (m, 6H).

The second aspect of Category V of the present disclosure relates to2-(thiazol-4-yl) compounds having the formula:

wherein R¹, R⁴, and L are further defined herein in Table X below.

TABLE X No. L R¹ R⁴ J360 —CH₂— phenyl methyl J361 —CH₂— phenyl ethylJ362 —CH₂— phenyl Phenyl J363 —CH₂— phenyl thiophen-2-yl J364 —CH₂—phenyl thiazol-2-yl J365 —CH₂— phenyl oxazol-2-yl J366 —CH₂— phenylisoxazol-3-yl J367 —CH₂— 3-chlorophenyl methyl J368 —CH₂— 3-chlorophenylethyl J369 —CH₂— 3-chlorophenyl phenyl J370 —CH₂— 3-chlorophenylthiophen-2-yl J371 —CH₂— 3-chlorophenyl thiazol-2-yl J372 —CH₂—3-chlorophenyl oxazol-2-yl J373 —CH₂— 3-chlorophenyl isoxazol-3-yl J374—CH₂— 3-methoxyphenyl methyl J375 —CH₂— 3-methoxyphenyl ethyl J376 —CH₂—3-methoxyphenyl phenyl J377 —CH₂— 3-methoxyphenyl thiophen-2-yl J378—CH₂— 3-methoxyphenyl thiazol-2-yl J379 —CH₂— 3-methoxyphenyloxazol-2-yl J380 —CH₂— 3-methoxyphenyl isoxazol-3-yl J381 —CH₂—3-fluorophenyl methyl J382 —CH₂— 3-fluorophenyl ethyl J383 —CH₂—3-fluorophenyl phenyl J384 —CH₂— 3-fluorophenyl thiophen-2-yl J385 —CH₂—3-fluorophenyl thiazol-2-yl J386 —CH₂— 3-fluorophenyl oxazol-2-yl J387—CH₂— 3-fluorophenyl isoxazol-3-yl J388 —CH₂— 2,5-dimethylthiazol-4-ylmethyl J389 —CH₂— 2,5-dimethylthiazol-4-yl ethyl J390 —CH₂—2,5-dimethylthiazol-4-yl phenyl J391 —CH₂— 2,5-dimethylthiazol-4-ylthiophen-2-yl J392 —CH₂— 2,5-dimethylthiazol-4-yl thiazol-2-yl J393—CH₂— 2,5-dimethylthiazol-4-yl oxazol-2-yl J394 —CH₂—2,5-dimethylthiazol-4-yl isoxazol-3-yl J395 —CH₂—2,4-dimethylthiazol-5-yl methyl J396 —CH₂— 2,4-dimethylthiazol-5-ylethyl J397 —CH₂— 2,4-dimethylthiazol-5-yl phenyl J398 —CH₂—2,4-dimethylthiazol-5-yl thiophen-2-yl J399 —CH₂—2,4-dimethylthiazol-5-yl thiazol-2-yl J400 —CH₂—2,4-dimethylthiazol-5-yl oxazol-2-yl J401 —CH₂— 2,4-dimethylthiazol-5-ylisoxazol-3-yl J402 —CH₂— 4-ethylthiazol-2-yl methyl J403 —CH₂—4-ethylthiazol-2-yl ethyl J404 —CH₂— 4-ethylthiazol-2-yl phenyl J405—CH₂— 4-ethylthiazol-2-yl thiophen-2-yl J406 —CH₂— 4-ethylthiazol-2-ylthiazol-2-yl J407 —CH₂— 4-ethylthiazol-2-yl oxazol-2-yl J408 —CH₂—4-ethylthiazol-2-yl isoxazol-3-yl J409 —CH₂—3-methyl-1,2,4-oxadiazol-5-yl methyl J410 —CH₂—3-methyl-1,2,4-oxadiazol-5-yl ethyl J411 —CH₂—3-methyl-1,2,4-oxadiazol-5-yl phenyl J412 —CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiophen-2-yl J413 —CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiazol-2-yl J414 —CH₂—3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl J415 —CH₂—3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl J416 —CH₂CH₂— phenyl methylJ417 —CH₂CH₂— phenyl ethyl J418 —CH₂CH₂— phenyl phenyl J419 —CH₂CH₂—phenyl thiophen-2-yl J420 —CH₂CH₂— phenyl thiazol-2-yl J421 —CH₂CH₂—phenyl oxazol-2-yl J422 —CH₂CH₂— phenyl isoxazol-3-yl J423 —CH₂CH₂—3-chlorophenyl methyl J424 —CH₂CH₂— 3-chlorophenyl ethyl J425 —CH₂CH₂—3-chlorophenyl phenyl J426 —CH₂CH₂— 3-chlorophenyl thiophen-2-yl J427—CH₂CH₂— 3-chlorophenyl thiazol-2-yl J428 —CH₂CH₂— 3-chlorophenyloxazol-2-yl J429 —CH₂CH₂— 3-chlorophenyl isoxazol-3-yl J430 —CH₂CH₂—3-methoxyphenyl methyl J431 —CH₂CH₂— 3-methoxyphenyl ethyl J432 —CH₂CH₂—3-methoxyphenyl phenyl J433 —CH₂CH₂— 3-methoxyphenyl thiophen-2-yl J434—CH₂CH₂— 3-methoxyphenyl thiazol-2-yl J435 —CH₂CH₂— 3-methoxyphenyloxazol-2-yl J436 —CH₂CH₂— 3-methoxyphenyl isoxazol-3-yl J437 —CH₂CH₂—3-fluorophenyl methyl J438 —CH₂CH₂— 3-fluorophenyl ethyl J439 —CH₂CH₂—3-fluorophenyl phenyl J440 —CH₂CH₂— 3-fluorophenyl thiophen-2-yl J441—CH₂CH₂— 3-fluorophenyl thiazol-2-yl J442 —CH₂CH₂— 3-fluorophenyloxazol-2-yl J443 —CH₂CH₂— 3-fluorophenyl isoxazol-3-yl J444 —CH₂CH₂—2,5-dimethylthiazol-4-yl methyl J445 —CH₂CH₂— 2,5-dimethylthiazol-4-ylethyl J446 —CH₂CH₂— 2,5-dimethylthiazol-4-yl phenyl J447 —CH₂CH₂—2,5-dimethylthiazol-4-yl thiophen-2-yl J448 —CH₂CH₂—2,5-dimethylthiazol-4-yl thiazol-2-yl J449 —CH₂CH₂—2,5-dimethylthiazol-4-yl oxazol-2-yl J450 —CH₂CH₂—2,5-dimethylthiazol-4-yl isoxazol-3-yl J451 —CH₂CH₂—2,4-dimethylthiazol-5-yl methyl J452 —CH₂CH₂— 2,4-dimethylthiazol-5-ylethyl J453 —CH₂CH₂— 2,4-dimethylthiazol-5-yl phenyl J454 —CH₂CH₂—2,4-dimethylthiazol-5-yl thiophen-2-yl J455 —CH₂CH₂—2,4-dimethylthiazol-5-yl thiazol-2-yl J456 —CH₂CH₂—2,4-dimethylthiazol-5-yl oxazol-2-yl J457 —CH₂CH₂—2,4-dimethylthiazol-5-yl isoxazol-3-yl J458 —CH₂CH₂— 4-ethylthiazol-2-ylmethyl J459 —CH₂CH₂— 4-ethylthiazol-2-yl ethyl J460 —CH₂CH₂—4-ethylthiazol-2-yl phenyl J461 —CH₂CH₂— 4-ethylthiazol-2-ylthiophen-2-yl J462 —CH₂CH₂— 4-ethylthiazol-2-yl thiazol-2-yl J463—CH₂CH₂— 4-ethylthiazol-2-yl oxazol-2-yl J464 —CH₂CH₂—4-ethylthiazol-2-yl isoxazol-3-yl J465 —CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl methyl J466 —CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl ethyl J467 —CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl phenyl J468 —CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiophen-2-yl J469 —CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiazol-2-yl J470 —CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl J471 —CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl

The compounds encompassed within the second aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in SchemeVIII and described in Example 9 below.

EXAMPLE 94-((S)-2-(2-(3-chlorophenypacetamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid (24)

Preparation of(S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)thiazol-4-yl]ethanaminehydrobromide salt (22): A mixture of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (7.74 g, 20mmol), and thiophen-2-carbothioic acid amide (3.14 g, 22 mmol) in CH₃CN(200 mL) is refluxed for 5 hours. The reaction mixture is cooled to roomtemperature and diethyl ether (50 mL) is added to the solution. Theprecipitate which forms is collected by filtration. The solid is driedunder vacuum to afford 7.14 g (87% yield) of the desired product. ESI+MS332 (M+1).

Preparation of2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}acetamide(23): To a solution of2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 22, (0.41g, 1 mmol) 3-chlorophenylacetic acid (0.170 g, 1 mmol) and1-hydroxybenzotriazole (HOBt) (0.070 g, 0.50 mmol) in DMF (5 mL) at 0°C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.190g, 1 mmol) followed by triethylamine (0.42mL, 3 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford 0.290 g (60% yield) of the desired product which isused without further purification. ESI−MS 482 (M−1).

Preparation of{4-[2-(3-chlorophenyl)acetylamino]-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid (24):2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene2-yl)thiazol-4-yl]ethyl}acetamide,23, (0.290 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.157 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.078 g of the desired product as the ammoniumsalt. ¹H NMR (CD3OD) δ 7.61 (d, 1H, J=3.6 Hz), 7.58 (d, 1H, J=5.1 Hz),7.41-7.35 (m, 1H), 7.28-7.22 (m, 2H), 7.18-6.98 (m, 6H), 5.33 (t, 1H,J=6.6 Hz), 3.70 (d, 2H, J=3.9 Hz), 3.23 (1H, A of ABX, J=6.6, 13.8 Hz),3.07 (1H, B of ABX, J=8.1, 13.5 Hz).

The following are non-limiting examples of compounds encompassed withinthe second aspect of Category V of the present disclosure.

4-((S)-2-(2-(3-Methoxyphenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.35 (d, 1H, J=8.7 Hz), 7.61-7.57 (m, 2H),7.25-7.20 (m, 2H), 7.25-7.20 (m, 2H), 7.09 (s, 1H), 7.05 (d, 2H, J=4.2Hz), 6.99 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=7.8 Hz), 6.77 (s, 1H),5.30-5.28 (m, 1H), 3.76 (s, 3H), 3.51 (s, 2H), 3.20 (1H, A of ABX,J=6.3, 13.6 Hz), 3.06 (1H, B of ABX, J=8.1, 13.8 Hz).

4-{(S)-2-(3-Phenylpropanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}-phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.30 (d, 1H, J=9 Hz), 7.61-7.56 (m, 2H),7.26-7.14 (m, 7H), 7.12 (d, 1H, J=1.5 Hz), 7.09 (d, 1H, J=2.1 Hz), 6.89(s, 1H), 5.28-5.26 (m, 1H), 3.18 (1H, A of ABX, J=6.2, 13.8 Hz), 2.96(1H, B of ABX, J=8.4, 13.6 Hz).

4-{(S)-2-(3-(3-Chlorophenyl)propanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.61-7.56 (m, 3H), 7.22-7.14 (m, 6H), 7.08 (d,1H), 7.00 (d, 1H, J=77.5 Hz), 6.870 (s, 1H), 5.25 (t, 1H, J=7.8 Hz),3.18 (1H, A of ABX, J=6.6, 13.8 Hz), 2.97 (1H, B of ABX, J=7.8, 13.8Hz), 2.87 (t, 2H, J=7.5 Hz), 2.51 (t, 2H, J=7.2 Hz).

4-{(S)-2-[2-3-Fluorophenyl)acetamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.61-7.57 (m, 2H), 7.32-7.28 (m, 1H), 7.19-7.16(m, 2H), 7.08 (t, 1H, J=4.5 Hz), 7.02-6.95 (m, 6H), 5.29 (t, 1H, J=8.1Hz), 3.53 (s, 2H), 3.22 (1H, A of ABX, J=6.6, 13.9 Hz), 3.06 (1H, B ofABX, J=8.4, 13.6 Hz).

(S)-4-{2-[2-3-Methyl-1,2,4-oxadiazol-5-yl)acetamido]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.98-7.95 (m, 2H), 7.48-7.46 (m, 3H), 7.23 (s,1H), 7.09-7.05 (m, 4H), 5.33 (t, 1H, J=7.2 Hz), 3.33-3.06 (m, 2H), 2.35(s, 3H).

4-{(S)-2-[2-(4-ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.62 (d, 1H, J=3 Hz), 7.58 (d, 1H, J=15.6 Hz),7.27 (s, 1H), 7.16 (t, 1H, J=1.5 Hz), 5.42-5.32 (m, 1H), 4.31 (d, 1H,J=15.6 Hz), 3.91 (d, 1H, J=15.9 Hz), 3.60-3.50 (m, 4H), 3.30-3.23 (m,2H), 2.98 (1H, B of ABX, J=9.9, 13.8 Hz), 1.21 (t, 3H, J=6.9 Hz).

The third aspect of Category V of the present disclosure relates tocompounds having the formula:

wherein the linking unit L comprises a phenyl unit, said linking grouphaving the formula:

—C(O)[(CR^(5a)H)][(CR^(6a)H )]—

R¹ is hydrogen, R^(6a) is phenyl, R^(5a) is phenyl or substituted phenyland non-limiting examples of the units R², R³, and R^(5a) are furtherexemplified below in Table XI.

TABLE XI No. R² R³ R^(5a) K472 methyl hydrogen phenyl K473 methylhydrogen 2-fluorophenyl K474 methyl hydrogen 3-fluorophenyl K475 methylhydrogen 4-fluorophenyl K476 methyl hydrogen 3,4-difluorophenyl K477methyl hydrogen 2-chlorophenyl K478 methyl hydrogen 3-chlorophenyl K479methyl hydrogen 4-chlorophenyl K480 methyl hydrogen 3,4-dichlorophenylK481 methyl hydrogen 2-methoxyphenyl K482 methyl hydrogen3-methoxyphenyl K483 methyl hydrogen 4-methoxyphenyl K484 ethyl hydrogenphenyl K485 ethyl hydrogen 2-fluorophenyl K486 ethyl hydrogen3-fluorophenyl K487 ethyl hydrogen 4-fluorophenyl K488 ethyl hydrogen3,4-difluorophenyl K489 ethyl hydrogen 2-chlorophenyl K490 ethylhydrogen 3-chlorophenyl K491 ethyl hydrogen 4-chlorophenyl K492 ethylhydrogen 3,4-dichlorophenyl K493 ethyl hydrogen 2-methoxyphenyl K494ethyl hydrogen 3-methoxyphenyl K495 ethyl hydrogen 4-methoxyphenyl

The compounds encompassed within the third aspect of Category V of thepresent disclosure can be prepared by the procedure outlined in SchemeIX and described in Example 10 herein below.

EXAMPLE 10(S)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid (26)

Preparation of(S)-N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-propanamide(25): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.95 g, 2.65 mmol), diphenylpropionic acid (0.60 g, 2.65 mmol) and1-hydroxybenzotriazole (HOBt) (0.180 g, 1.33 mmol) in DMF (10 mL) at 0°,is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.502 g,2.62 mmol) followed by triethylamine (1.1 mL, 7.95 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford 0.903 g (70% yield) of the desired product which isused without further purification.

Preparation of(S)-4-(2-(2,3-diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (26)(S)-N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-propanamide,25, (0.903 g) is dissolved in MeOH (10 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (30 mL) and treated with SO₃-pyridine(0.621 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.415 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD) δ 8.59-8.52 (m, 1H), 7.37-7.04 (m, 9H), 6.97-6.93(m, 1H), 6.89-6.85 (m, 2H), 5.36-5.32 (m, 1H), 3.91-3.83 (m, 1H), 3.29(1H, A of ABX, obscured by solvent), 3.15 (1H, B of ABX, J=5.4, 33.8Hz), 2.99-2.88 (m, 2H), 2.81-2.69 (m, 2H), 1.32-1.25 (m, 3H).

The following procedure illustrates an example of the procedure whichcan be used to provide different R^(5a) units according to the presentdisclosure. Using the procedure outlined in Scheme X and described inExample 11, one can achieve the R^(5a) units encompassed by the presentdisclosure.

EXAMPLE 11 2-(2-Methoxyphenyl)-3-phenylpropanoic acid (28)

Preparation of methyl 2-(2-methoxyphenyl)-3-phenylpropanoate (27): A500mL round-bottom flask is charged with methyl2-(2-methoxyphenyl)acetate (8.496 g, 47 mmol, 1 eq) and THF (200mL). Thehomogeneous mixture is cooled to 0° C. in an ice bath. Lithiumdiisopropyl amide (23.5mL of a 2.0M solution in heptane/THF) is added,maintaining a temperature less than 3° C. The reaction is stirred 45minutes at this reduced temperature. Benzyl bromide (5.6mL, 47 mmo1, 1eq) is added dropwise. The reaction is allowed to gradually warm to roomtemperature and is stirred for 18 hours. The reaction is quenched with1N HCl and extracted 3 times with equal portions of EtOAc. The combinedextracts are washed with H₂O and brine, dried over Na₂SO₄, filtered, andconcentrated. The residue is purified over silica to afford 4.433 g(35%) of the desired compound. ESI+MS 293 (M+Na).

Preparation of 2-(2-methoxyphenyl)-3-phenylpropanoic acid (28): Methyl2-(2-methoxyphenyl)-3-phenylpropanoate (4.433 g, 16 mmol, 1 eq) isdissolved in 100mL of a 1:1(v:v) mixture of THF and methanol. Sodiumhydroxide (3.28 g, 82 mmol, 5 eq) is added and the reaction mixture isstirred 18 hours at room temperature. The reaction is then poured intoH₂O and the pH is adjusted to 2 via addition of 1N HCl. A whiteprecipitate forms which is removed by filtration. The resulting solutionis extracted with 3 portion of diethyl ether. The extracts are pooled,washed with H₂O and brine, dried over Na₂SO₄, filtered, and concentratedin vacuo. The resulting residue is purified over silica to afford 2.107g (51%) of the desired compound. ESI−MS 255 (M−1), 211 (M—CO₂H).

Intermediate 28 can be carried forward according to the procedureoutlined in Scheme IX and described in Example 10 to produce thefollowing compound according to the third aspect of Category V.

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.32-7.12 (m, 7H), 7.05-7.02 (m, 1H), 6.99-6.83(m, 4H), 6.80-6.75 (m, 2H), 5.35-5.31 (m, 1H), 4.31-4.26 (m, 1H), 3.75(s, 3H), 3.20-2.90 (m, 4H), 2.79-2.74 (m, 2H), 1.32-1.25 (m, 3H).

The following are further non-limiting examples of compounds accordingto the third aspect of Category I of the present disclosure.

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-fluorophenyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.33-6.87 (m, 14H), 5.39-5.25 (m, 1H), 3.95-3.83(m, 1H), 3.31-3.10 (m, 1H), 3.05-2.88 (m, 2H), 2.80-2.70 (m, 2H),1.32-1.23 (m, 3H). ¹⁹F NMR □47.59.

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.85 (d, 1H, J=8.4 Hz), 7.25-7.20 (m, 1H),7.11-7.02 (m, 4H), 7.01 (s, 1H), 6.90-6.79 (m, 2H), 5.45-5.40 (m, 1H),4.09 (s, 2H), 3.79 (s, 3H), 3.12-3.08 (m, 2H), 1.10 (s, 9H).

The fourth aspect of Category V of the present disclosure relates tocompounds having the formula:

wherein the linking unit L comprises a phenyl unit, said linking grouphaving the formula:

—C(O)[(CR^(5a)H)][(CR^(6a)H]—

R¹ is hydrogen, R^(6a) is phenyl, R^(5a) is substituted or unsubstitutedheteroaryl and the units R², R³, and R^(5a) are further exemplifiedherein below in Table XII.

TABLE XII No. R² R³ R^(5a) L496 methyl hydrogen3-methyl-1,2,4-oxadiazol-5-yl L497 methyl hydrogen thiophen-2-yl L498methyl hydrogen thiazol-2-yl L499 methyl hydrogen oxazol-2-yl L500methyl hydrogen isoxazol-3-yl L501 ethyl hydrogen3-methyl-1,2,4-oxadiazol-5-yl L502 ethyl hydrogen thiophen-2-yl L503ethyl hydrogen thiazol-2-yl L504 ethyl hydrogen oxazol-2-yl L505 ethylhydrogen isoxazol-3-yl L506 ethyl methyl 3-methyl-1,2,4-oxadiazol-5-ylL507 ethyl methyl thiophen-2-yl L508 ethyl methyl thiazol-2-yl L509ethyl methyl oxazol-2-yl L510 ethyl methyl isoxazol-3-yl L511thiophen-2-yl hydrogen 3-methyl-1,2,4-oxadiazol-5-yl L512 thiophen-2-ylhydrogen thiophen-2-yl L513 thiophen-2-yl hydrogen thiazol-2-yl L514thiophen-2-yl hydrogen oxazol-2-yl L515 thiophen-2-yl hydrogenisoxazol-3-yl L516 isoxazol-3-yl hydrogen 3-methyl-1,2,4-oxadiazol-5-ylL517 isoxazol-3-yl hydrogen thiophen-2-yl L518 isoxazol-3-yl hydrogenthiazol-2-yl L519 isoxazol-3-yl hydrogen oxazol-2-yl L520 isoxazol-3-ylhydrogen isoxazol-3-yl

The compounds encompassed within the fourth aspect of Category V of thepresent disclosure can be prepared by the procedure outlined in SchemeXI and described in Example 5 herein below.

EXAMPLE 124-{(S)-2-(4-Ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamido]ethyl}phenylsulfamicacid (31)

Preparation ofethyl-2-benzyl-3-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)-ethylamino]-3-oxopropanoate(29): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.406 g, 1.13 mmol), 2-benzyl-3-ethoxy-3-oxopropanoic acid (0.277 g)and 1-hydroxybenzotriazole (HOBt) (0.191 g, 1.41 mmol) in DMF (10 mL) at0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.240g, 1.25 mmol) followed by diisopropylethylamine (DIPEA) (0.306 g). Themixture is stirred at 0° C. for 30 minutes then at room temperatureovernight. The reaction mixture is diluted with water and extracted withEtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5%aqueous NaHCO₃, water and brine, and dried over Na₂SO₄. The solvent isremoved in vacuo to afford 0.169 g (31% yield) of the desired productwhich is used without further purification.

Preparation ofN-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide(30): Ethyl2-benzyl-3-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoateis dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate(80 mg) and acetamide oxime (43 mg) are added. and treated with 80 mgpotassium carbonate and 43 mg acetamide oxime at reflux. The reactionmixture is cooled to room temperature, filtered and concentrated. Theresidue is chromatographed over silica to afford 0.221 g (94%) of thedesired product as a yellow oil.

Preparation of4-{(S)-2-(4-ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamido]ethyl}phenylsulfamicacid (31):N-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide,30, (0.221 g) and tin (II) chloride (507 mg, 2.2 mmol) are dissolved inEtOH (25 mL) and the solution is brought to reflux 4 hours. The solventis removed in vacuo and the resulting residue is dissolved in EtOAc. Asaturated solution of NaHCO₃ (50 mL) is added and the solution isstirred 1 hour. The organic layer is separated and the aqueous layerextracted twice with EtOAc. The combined organic layers are dried(Na₂SO₄), filtered and concentrated to a residue which is dissolved inpyridine (0.143 g) and treated with SO₃-pyridine (0.143 g). The reactionis stirred at room temperature for 5 minutes after which a 7% solutionof NH₄OH is added. The mixture is then concentrated and the resultingresidue is purified by reverse phase chromatography to afford 0.071 g ofthe desired product as the ammonium salt. ¹H NMR (CD₃OD): δ 7.29-6.87(m, 10H), 5.38-5.30 (m, 1H), 4.37-4.30 (m, 1H), 3.42-2.74 (m, 6H),2.38-2.33 (m, 3H), 1.34-1.28 (m, 3H).

Category VI of the present disclosure relates to 2-(thiazol-2-yl)compounds having the formula:

wherein R¹, R², and R³ are further defined herein in Table XIII herein.

TABLE XIII No. R² R³ R¹ M521 ethyl hydrogen thiophen-2-yl M522 ethylhydrogen thiazol-2-yl M523 ethyl hydrogen oxazol-2-yl M524 ethylhydrogen isoxazol-3-yl M525 ethyl hydrogen imidazol-2-yl M526 ethylhydrogen isoxazol-3-yl M527 ethyl hydrogen oxazol-4-yl M528 ethylhydrogen isoxazol-4-yl M529 ethyl hydrogen thiophen-4-yl M530 ethylhydrogen thiazol-4-yl M531 ethyl methyl methyl M532 ethyl methyl ethylM533 ethyl methyl propyl M534 ethyl methyl iso-propyl M535 ethyl methylbutyl M536 ethyl methyl phenyl M537 ethyl methyl benzyl M538 ethylmethyl 2-fluorophenyl M539 ethyl methyl 3-fluorophenyl M540 ethyl methyl4-fluorophenyl M541 phenyl hydrogen methyl M542 phenyl hydrogen ethylM543 phenyl hydrogen propyl M544 phenyl hydrogen iso-propyl M545 phenylhydrogen butyl M546 phenyl hydrogen phenyl M547 phenyl hydrogen benzylM548 phenyl hydrogen 2-fluorophenyl M549 phenyl hydrogen 3-fluorophenylM550 phenyl hydrogen 4-fluorophenyl M551 thiophen-2-yl hydrogen methylM552 thiophen-2-yl hydrogen ethyl M553 thiophen-2-yl hydrogen propylM554 thiophen-2-yl hydrogen iso-propyl M555 thiophen-2-yl hydrogen butylM556 thiophen-2-yl hydrogen phenyl M557 thiophen-2-yl hydrogen benzylM558 thiophen-2-yl hydrogen 2-fluorophenyl M559 thiophen-2-yl hydrogen3-fluorophenyl M560 thiophen-2-yl hydrogen 4-fluorophenyl

The compounds encompassed within Category VI of the present disclosurecan be prepared by the procedure outlined in Scheme XII and described inExample 13 below.

EXAMPLE 13(S)-4-[2-(4-Ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)ethyl]-phenylsulfamicacid (33)

Preparation of(S)-N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-4-oxo-4-phenylbutanamide(32): 3-Benzoylpropionic acid (0.250 g) is dissolved in CH₂Cl₂ (5 mL),N-methyl imidazole (0.333 mL) is added and the resulting solution iscooled to 0° C. after which a solution of thionyl chloride (0.320 g) inCH₂Cl₂ (2 mL) is added dropwise. After 0.5 hours(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethanamine, 3, (0.388 g) isadded. The reaction is stirred for18 hours at room temperature and thenconcentrated in vacuo. The resulting residue is dissolved in EtOAc andwashed with 1N HCl and brine. The solution is dried over Na₂SO₄,filtered, and concentrated and the crude material purified over silicato afford 0.415 g of the desired product.

Preparation of(S)-4-[2-(4-ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)-ethyl]phenylsulfamicacid (33):(S)-N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-propanamide,32, (0.2 g) is dissolved in MeOH (15 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (5 mL) and treated with SO₃-pyridine(0.153 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.090 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD) δ 8.68 (d, 1H, J=8.2 Hz), 8.00 (d, 2H, J=7.2 Hz),7.80-7.50 (m, 3H), 7.12 (s, 4H), 7.03 (s, 1H), 5.46-5.38 (m, 1H),3.29-3.14 (m, 2H), 3.06-2.99 (m, 2H), 2.83 (q, 2H, J=7.5 Hz), 2.69-2.54(m, 2H), 1.33 (t, 3H, J=7.5 Hz).

The following are non-limiting examples of compounds encompassed withinCategory II of the present disclosure. The intermediate nitro compoundsof the following can be prepared by coupling the appropriate4-oxo-carboxcylic acid with intermediate 3 under the conditionsdescribed herein above for the formation of intermediate 4 of scheme I.

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(5-methyl-4-oxohexanamido)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.59 (d, 1H, J=8.1 Hz), 7.14 (s, 4H), 7.08 (t,1H, J=13.0 Hz), 5.40-5.35 (m, 1H), 3.37-3.27 (m, 2H), 3.04-2.97 (m, 1H),2.83-2.61 (m, 4H), 2.54-2.36 (m, 3H), 1.33 (t, 2H, J=7.3 Hz), 1.09 (dd,6H, J=7.0, 2.2 Hz).

(S)-4-{2-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR(CD₃OD) δ 8.64 (d, 1H, J=8.4 Hz), □07.60□□d, 2H, J=10.6 Hz),7.11 (s, 3H), 7.04 (d, 2H, J=5.5 Hz), 5.42-5.40 (m, 1H), 4.30-4.22 (m,4H), 3.20-2.98 (m, 4H), 2.82 (q, 2H, J=7.3 Hz), 2.67-2.48 (m, 2H), 2.23(t, 2H, J=5.5 Hz), 1.32 (t, 3H, J=7.3 Hz).

(S)-4-{2-[4-(2,3-Dimethoxyphenyl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD), δ 8.64 (d, 1H, J=8.1 Hz), 7.21-7.11 (m, 7H), 7.02(s, 1H), 5.42 (q, 1H, J=5.9 Hz), 3.90 (d, 3H, J=3.3 Hz), 3.88 (d, 3H,J=2.9 Hz), 3.22-3.18 (m, 2H), 3.07-2.99 (m, 2H), 2.83 (q, 2H, J=7.3 Hz),2.63-2.54 (m, 2H), 1.34 (t, 3H, J=7.69 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamido]ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.60 (d, 1H, J=12.8 Hz), 7.91-7.81 (m, 2H),7.48-7.44 (m, 1H), 7.22-7.21 (m, 1H), 6.99 (s, 3H), 6.91 (s, 1H), 5.30(q, 1H, J=5.4 Hz), 3.36 (q, 2H, J=7.0 Hz), 3.21-3.15 (m, 1H), 2.91-2.85(m, 1H), 2.74 (q, 2H, J=10.4 Hz), 2.57-2.50 (m, 2H), 1.20 (t, 3H, J=7.5Hz).

(S)-4-{2-[4-(2,3-dihydrobenzo [b][1,4]dioxin-6-yl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid: ¹HNMR (CD₃OD) δ 7.52-7.47 (m,2 H), 7.11(s,4H), 7.03 (s,1H), 6.95 (d, 1H,J=8.4 Hz), 5.41 (q, 1H, J=3.7 Hz), 4.31 (d, 4H, J=5.5 Hz), 3.24-3.12 (m,2H), 3.06-2.98 (m, 2H), 2.83 (q, 2H, J=7.3 Hz), 2.62-2.53 (m, 2H), 1.33(t, 3H, J=7.3 Hz).

(S)-4-[2-(4-tert-butoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamicacid: ¹H NMR (CD₃OD), δ 7.10 (s 4H), 7.02 (s, 1H), 5.41 (q, 1H, J=3.7Hz), 3.30-3.25 (m, 1H), 3.06-2.99 (m, 1H), 2.83 (q, 2H, J=7.3 Hz),2.52-2.40 (m, 4H), 1.42 (s, 9H), 1.33 (t, 3H, J=7.3 Hz).

(S)-4-[2-(4-ethoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.62 (d, 1H, J=8.4 Hz), 7.10 (s, 4H), 7.02 (s,1H), 5.40 (q,1H, 3.7 Hz), 4.15 (q, 2H, J=7.3 Hz), 3.28-3.25 (m, 1H),3.05-3.02 (m, 1H), 2.82 (q, 2H, J=4.4 Hz), 2.54-2.48 (m, 2H), 1.33 (t,3H, J=7.3 Hz), 1.24 (t, 3H, J=7.0 Hz).

The first aspect of Category VII of the present disclosure relates to2-(thiazol-2-yl) compounds having the formula:

wherein non-limiting examples of R¹, R², and R³ are further describedbelow in Table XIV.

TABLE XIV No. R² R³ R¹ N561 methyl hydrogen phenyl N562 methyl hydrogenbenzyl N563 methyl hydrogen 2-fluorophenyl N564 methyl hydrogen3-fluorophenyl N565 methyl hydrogen 4-fluorophenyl N566 methyl hydrogen2-chlorophenyl N567 methyl hydrogen 3-chlorophenyl N568 methyl hydrogen4-chlorophenyl N569 ethyl hydrogen phenyl N570 ethyl hydrogen benzylN571 ethyl hydrogen 2-fluorophenyl N572 ethyl hydrogen 3-fluorophenylN573 ethyl hydrogen 4-fluorophenyl N574 ethyl hydrogen 2-chlorophenylN575 ethyl hydrogen 3-chlorophenyl N576 ethyl hydrogen 4-chlorophenylN577 thiene-2-yl hydrogen phenyl N578 thiene-2-yl hydrogen benzyl N579thiene-2-yl hydrogen 2-fluorophenyl N580 thiene-2-yl hydrogen3-fluorophenyl N581 thiene-2-yl hydrogen 4-fluorophenyl N582 thiene-2-ylhydrogen 2-chlorophenyl N583 thiene-2-yl hydrogen 3-chlorophenyl N584thiene-2-yl hydrogen 4-chlorophenyl

The compounds encompassed within Category VII of the present disclosurecan be prepared by the procedure outlined in Scheme XIII and describedin Example 14 herein below.

EXAMPLE 14(S)-4-(2-(3-Benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (35)

Preparation of(S)-1-benzyl-3-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea(34): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.360 g, 1 mmol) and Et₃N (0.42 mL, 3 mmol) in 10 mL CH₂Cl₂ is addedbenzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at roomtemperature for 18 hours. The product is isolated by filtration toafford 0.425 g (96% yield) of the desired product which is used withoutfurther purification.

Preparation of(S)-4-(2-(3-benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (35):(S)-1-benzyl-3-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea, 34,(0.425 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10%w/w) is added and the mixture is stirred under a hydrogen atmosphere 18hours. The reaction mixture is filtered through a bed of CELITE™ and thesolvent is removed under reduced pressure. The crude product isdissolved in pyridine (12 mL) and treated with SO₃-pyridine (0.220 g).The reaction is stirred at room temperature for 5 minutes after which a7% solution of NH₄OH is added. The mixture is then concentrated and theresulting residue is purified by reverse phase chromatography to afford0.143 g of the desired product as the ammonium salt. ¹H NMR (CD₃OD) δ7.32-7.30 (m, 2H), 7.29-7.22 (m, 3H), 7.12-7.00 (m, 4H), 6.84 (d, 1H,J=8.1 Hz), 5.35-5.30 (m, 1H), 4.29 (s, 2H), 3.27-3.22 (m, 3H), 3.11-3.04(m, 3H), 2.81 (q, 2H, J=10.2, 13.0 Hz), 1.31 (t, 3H, J=4.5 Hz).

The following is a non-limiting examples of compounds encompassed withinthe first aspect of Category VII of the present disclosure.

4-{[(S)-2-(2-Ethylthiazol-4-yl)-2-(3-(R)-methoxy-1-oxo-3-phenylpropan-2-yl)ureido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.36-7.26 (m, 3H), 7.19-7.17 (m, 2H), 7.10-7.06(m, 2H), 6.90-6.86 (m, 3H), 5.12-5.06 (m, 1H), 4.60-4.55 (m, 1H), 3.69(s, 3H) 3.12-2.98 (m, 6H), 1.44-1.38 (m, 3H).

The second aspect of Category VII of the present disclosure relates to2-(thiazol-4-yl) compounds having the formula:

wherein non-limiting examples of R¹ and R⁴ are further described belowin Table XV.

TABLE XV No. R¹ R⁴ O585 Methyl methyl O586 Ethyl methyl O587 n-propylmethyl O588 iso-propyl methyl O589 Phenyl methyl O590 Benzyl methyl O5912-fluorophenyl methyl O592 2-chlorophenyl methyl O593 thiophen-2-ylmethyl O594 thiazol-2-yl methyl O595 oxazol-2-yl methyl O596isoxazol-3-yl methyl O597 Methyl ethyl O598 Ethyl ethyl O599 n-propylethyl O600 iso-propyl ethyl O601 Phenyl ethyl O602 Benzyl ethyl O6032-fluorophenyl ethyl O604 2-chlorophenyl ethyl O605 thiophen-2-yl ethylO606 thiazol-2-yl ethyl O607 oxazol-2-yl ethyl O608 isoxazol-3-yl ethylO609 Methyl thiophen-2-yl O610 Ethyl thiophen-2-yl O611 n-propylthiophen-2-yl O612 iso-propyl thiophen-2-yl O613 Phenyl thiophen-2-ylO614 Benzyl thiophen-2-yl O615 2-fluorophenyl thiophen-2-yl O6162-chlorophenyl thiophen-2-yl O617 thiophen-2-yl thiophen-2-yl O618thiazol-2-yl thiophen-2-yl O619 oxazol-2-yl thiophen-2-yl O620isoxazol-3-yl thiophen-2-yl O621 Methyl thiazol-2-yl O622 Ethylthiazol-2-yl O623 n-propyl thiazol-2-yl O624 iso-propyl thiazol-2-ylO625 Phenyl thiazol-2-yl O626 Benzyl thiazol-2-yl O627 2-fluorophenylthiazol-2-yl O628 2-chlorophenyl thiazol-2-yl O629 thiophen-2-ylthiazol-2-yl O630 thiazol-2-yl thiazol-2-yl O631 oxazol-2-ylthiazol-2-yl O632 isoxazol-3-yl thiazol-2-yl O633 Methyl oxazol-2-ylO634 Ethyl oxazol-2-yl O635 n-propyl oxazol-2-yl O636 iso-propyloxazol-2-yl O637 Phenyl oxazol-2-yl O638 Benzyl oxazol-2-yl O6392-fluorophenyl oxazol-2-yl O640 2-chlorophenyl oxazol-2-yl O641thiophen-2-yl oxazol-2-yl O642 thiazol-2-yl oxazol-2-yl O643 oxazol-2-yloxazol-2-yl O644 isoxazol-3-yl oxazol-2-yl

The compounds encompassed within the second aspect of Category VII ofthe present disclosure can be prepared by the procedure outlined inScheme XIV and described in Example 14 below.

EXAMPLE 154-{(S)-2-(3-Benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamicacid (37)

Preparation of1-benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}urea(36): To a solution of(S)-2-(4-nitrophenyl)-1-[(2-thiophen-2-yl)thiazol-4-yl)ethan-aminehydrobromide salt, 8, and Et₃N (0.42mL, 3 mmol) in 10 mL DCM is addedbenzyl isocyanate (0.12mL, 1 mmol). The mixture is stirred at roomtemperature for 18 hours. The product is isolated by filtration toafford 0.445 g (96% yield) of the desired product which is used withoutfurther purification.

Preparation of4-{(S)-2-(3-benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (37):1-Benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}urea,36, (0.445 g) is dissolved in MeOH (10 mL) and CH₂Cl₂ (5 mL). Acatalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 18 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (12 mL) and treatedwith SO₃-pyridine (0.110 g). The reaction is stirred at room temperaturefor 5 minutes after which a 7% solution of NH₄OH is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford 0.080 g of the desired product as theammonium salt. ¹H NMR (CD₃OD) δ 7.61 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=6Hz), 7.33-7.22 (m, 4H), 7.17-7.14 (m, 1H), 7.09-6.94 (m, 6H), 5.16 (t,1H, J=6.6 Hz), 4.13 (s, 2H), 3.14-3.11 (m, 2H).

Category VIII of the present disclosure relates to 2-(thiazol-4-yl)compounds having the formula:

wherein R¹, R⁴, and L are further defined herein in Table XVI hereinbelow.

TABLE XVI No. R⁴ L R¹ P645 methyl —SO₂— methyl P646 ethyl —SO₂— methylP647 phenyl —SO₂— methyl P648 thiophen-2-yl —SO₂— methyl P649 methyl—SO₂— trifluoromethyl P650 ethyl —SO₂— trifluoromethyl P651 phenyl —SO₂—trifluoromethyl P652 thiophen-2-yl —SO₂— trifluoromethyl P653 methyl—SO₂— ethyl P654 ethyl —SO₂— ethyl P655 phenyl —SO₂— ethyl P656thiophen-2-yl —SO₂— ethyl P657 methyl —SO₂— 2,2,2-trifluoroethyl P658ethyl —SO₂— 2,2,2-trifluoroethyl P659 phenyl —SO₂— 2,2,2-trifluoroethylP660 thiophen-2-yl —SO₂— 2,2,2-trifluoroethyl P661 methyl —SO₂— phenylP662 ethyl —SO₂— phenyl P663 phenyl —SO₂— phenyl P664 thiophen-2-yl—SO₂— phenyl P665 methyl —SO₂— 4-fluorophenyl P666 ethyl —SO₂—4-fluorophenyl P667 phenyl —SO₂— 4-fluorophenyl P668 thiophen-2-yl —SO₂—4-fluorophenyl P669 methyl —SO₂— 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P670 ethyl —SO₂— 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P671 phenyl —SO₂— 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P672 thiophen-2-yl —SO₂— 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P673 methyl —SO₂— 1-methyl-1H-imidazol-4-ylP674 ethyl —SO₂— 1-methyl-1H-imidazol-4-yl P675 phenyl —SO₂—1-methyl-1H-imidazol-4-yl P676 thiophen-2-yl —SO₂—1-methyl-1H-imidazol-4-yl P678 methyl —SO₂— 4-acetamidophenyl P679 ethyl—SO₂— 4-acetamidophenyl P680 phenyl —SO₂— 4-acetamidophenyl P681thiophen-2-yl —SO₂— 4-acetamidophenyl P682 methyl —SO₂CH₂— phenyl P683ethyl —SO₂CH₂— phenyl P684 phenyl —SO₂CH₂— phenyl P685 thiophen-2-yl—SO₂CH₂— phenyl P686 methyl —SO₂CH₂— (4-methylcarboxy- phenyl)methylP687 ethyl —SO₂CH₂— (4-methylcarboxy- phenyl)methyl P688 phenyl —SO₂CH₂—(4-methylcarboxy- phenyl)methyl P689 thiophen-2-yl —SO₂CH₂—(4-methylcarboxy- phenyl)methyl P690 methyl —SO₂CH₂— (2-methylthiazol-4-yl)methyl P691 ethyl —SO₂CH₂— (2-methylthiazol- 4-yl)methyl P692phenyl —SO₂CH₂— (2-methylthiazol- 4-yl)methyl P693 thiophen-2-yl—SO₂CH₂— (2-methylthiazol- 4-yl)methyl P694 methyl —SO₂CH₂CH₂— phenylP695 ethyl —SO₂CH₂CH₂— phenyl P696 phenyl —SO₂CH₂CH₂— phenyl P697thiophen-2-yl —SO₂CH₂CH₂— phenyl

The compounds encompassed within Category VIII of the present disclosurecan be prepared by the procedure outlined in Scheme XV and described inExample 16 herein below.

EXAMPLE 16{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid (39)

Preparation of (S)-N-{2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-1-phenylmethanesulfonamide(38): To a suspension of2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 8, (330 mg,0.80 mmol) in CH₂Cl₂ (6 mL) at 0° C. is added diisopropylethylamine(0.30 mL, 1.6 mmol) followed by phenylmethanesulfonyl chloride (167 mg,0.88 mmol). The reaction mixture is stirred at room temperature for 14hours. The mixture is diluted with CH₂Cl₂ and washed with sat. NaHCO₃followed by brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The resulting residue is purified over silica to afford 210 mg of thedesired product as a white solid.

Preparation of{4-(S)-[2-phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid (39): (S)-N-{2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-1-phenylmethanesulfonamide,38, (210 mg, 0.41 mmol) is dissolved in MeOH (4 mL). A catalytic amountof Pd/C (10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(197 mg, 1.23 mmol). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.060 g of the desired product as the ammoniumsalt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.52 — 7.63 (m, 6.70-7.28 (m, 11H),4.75 (t, J=7.2 Hz, 1H), 3.95-4.09 (m, 2H), 3.20 (dd, J=13.5 and 7.8 Hz,1H), 3.05 (dd, J=13.5 and 7.8 Hz, 1H). 1013770

Intermediates for use in Step (a) of Scheme XV can be convenientlyprepared by the procedure outlined herein below in Scheme XVI anddescribed in Example 17.

EXAMPLE 17 (2-Methylthiazol-4-yl)methanesulfonyl chloride (41)

Preparation of sodium (2-methylthiazol-4-yl)methanesulfonate (40):4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) is dissolved in H₂O(2 mL) and treated with sodium sulfite (224 mg, 1.78 mmol). The reactionmixture is subjected to microwave irradiation for 20 minutes at 200° C.The reaction mixture is diluted with H₂O (30 mL) and washed with EtOAc(2×25 mL). The aqueous layer is concentrated to afford 0.368 g of thedesired product as a yellow solid. LC/MS ESI+194 (M+1, free acid).

Preparation of (2-methylthiazol-4-yl)methanesulfonyl chloride (41):Sodium (2-methylthiazol-4-yl)methanesulfonate, 40, (357 mg, 1.66 mmol)is dissolved in phosphorous oxychloride (6 mL) and is treated withphosphorous pentachloride (345 mg, 1.66 mmol). The reaction mixture isstirred at 50° C. for 3 hours, then allowed to cool to room temperature.The solvent is removed under reduced pressure and the residue isre-dissolved in CH₂Cl₂ (40 mL) and is washed with sat. NaHCO₃ and brine.The organic layer is dried over MgSO₄, filtered, and the solvent removedin vacuo to afford 0.095 g of the desired product as a brown oil. LC/MSESI+211 (M+1). Intermediates are obtained in sufficient purity to becarried forward according to Scheme IX without the need for furtherpurification.

4-{(S)-2-[(2-methylthiazol-4-yl)methylsulfonamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.71-7.66 (m, 2H), 7.27-7.10 (m, 7H), 4.87 (t,1H, J=7.3 Hz), 4.30-4.16 (q, 2H, J=13.2 Hz), 3.34-3.13 (m, 2H), 2.70 (s,3H).

The following are non-limiting examples of compounds encompassed withinCategory VIII of the present disclosure.

{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}-sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.27 — 7.32 (m, 3H), 7.16-7.20 (m,3H), 7.05-7.6 (m, 2H), 6.96 (d, J=8.4 Hz, 2H), 4.70 (t, J=9.0 Hz, 1H),3.91-4.02 (m, 2H), 2.95-3.18 (m, 4H), 1.41 (t, J=7.5 Hz, 3H).

{4-(S)-[2-(3-Methoxyphenyl)methanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}sulfamicacid: ¹H-NMR (300 MHz, MeOH-d₄) δ 7.20 t, J=8.1 Hz. 1H), 6.94-7.08(m,4H), 6.88-6.94 (m, 3H), 6.75-6.80 (m, 1H), 4.67 (t, J=7.2 Hz, 1H),3.90-4.0 (m, 2H), 3.76 (s, 3H), 2.95-3.16 (m, 4H), 1.40 (t, J=7.5 HZ,3H).

(S)-4-{[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylsulfamoyl]methyl}-benzoicacid methyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 7.90 — 7.94 — (m, 2H),7.27-7.30 (m, 2H), 7.06-7.11 (m, 3H), 6.97-7.00 (m, 2H), 4.71 (t, J=7.2Hz, 1H), 3.95-4.08 (4, 2H), 3.92 (s, 3H), 2.80-3.50 (m, 4H), 1.38-1.44(m, 3H).

(S)-4-[2-(2-Ethylthiazol-4-yl)-2-(1-methyl-1H-imidazol-4-sulfonamido)ethyl]-phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.54 (s, 1H, 7.20 (s, 1H), 7.09 (s,1H), 6.92-7.00 (m, 4H), 4.62 (t, J=5.4 Hz, 1H), 3.70 (s, 3H), 2.98-3.14(m,3H), 2.79 (dd, J=9.3 and 15.0 Hz, 1H), 1.39 (q, J=7.5 Hz, 3H).

4-{(S)-2-[2-(Thiophen-2-yl)thiazol-4-yl]-2-(2,2,2-trifluoroethylsulfonamido)-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.62-7.56 (m, 2H), 7.22 (s, 1H), 7.16-7.06 (m,5H), 4.84 (t, 1H, J=7.6 Hz), 3.71-3.62 (m, 2H), 3.32-3.03 (m, 2H).

{4-(S)-[2-(Phenylethanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]-phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) 7.56-7.62 (m, 2H), 7.04 — 7.19 (m, 9H),6.94-6.97 (m, 2H), 4.78 (t, J=7.8 Hz, 1H), 3.22-3.30 (m, 2H)), 3.11 (dd,J=13.5 and 7.8 Hz, 1H), 2.78-2.87 (m, 4H).

{4-(S)-[3-(Phenylpropanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]-phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.56-7.62 (m, 2H), 6.99-7.17 (m, 10H),4.72 (t, J=7.8 Hz, 1H), 3.21 (dd, J=13.5 and 7.2 Hz, 1H), 3.02 (dd,J=13.5 and 7.2 Hz, 1H), 2.39-2.64 (m, 4H), 1.65-1.86 (m, 2H).

(S)-{4-[2-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonylamino)-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.53 (d, J=5.1 Hz, 1H) 7.48 (d, J=5.1Hz, 1H), 7.13-7.10 (m, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.93-6.88 (m, 3H),6.75 (d, J=8.1 Hz, 1H), 6.54 (d, J=8.1 Hz, 1H), 4.61 (t, J=7.5 Hz, 1H),4.20-4.08 (m, 2H), 3.14-3.00 (m, 4H), 2.69 (s, 3H).

4-{(S)-2-(4-acetamidophenylsulfonamido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.67-7.52 (m, 6H), 7.24-7.23 (m, 1H), 7.12-7.09(m, 3H), 7.02-6.99 (m, 2H), 4.70 (t, 1H, J=7.3 Hz), 3.25-3.00 (m, 2H),2.24 (s, 3H).

The first aspect of Category IX of the present disclosure relates tocompounds having the formula:

wherein R¹ is a substituted or unsubstituted heteroaryl and R⁴ is C₁-C₆linear, branched, or cyclic alkyl as further described herein below inTable XVII.

TABLE XVII No. R⁴ R¹ Q698 —CH₃ 4-(methoxycarbonyl)thiazol-5-yl Q699 —CH₃4-[(2-methoxy-2- oxoethyl)carbamoyl]thiazol-5-yl Q700 —CH₃5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl Q701 —CH₃5-(2-methoxyphenyl)oxazol-2-yl Q702 —CH₃5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl Q703 —CH₃5-[4-(methylcarboxy)phenyl]oxazol-2-yl Q704 —CH₃5-(3-methoxybenzyl)oxazol-2-yl Q705 —CH₃ 5-(4-phenyl)oxazol-2-yl Q706—CH₃ 5-(2-methoxyphenyl)thiazol-2-yl Q707 —CH₃5-(3-methoxyphenyl)thiazol-2-yl Q708 —CH₃ 5-(4-fluorophenyl)thiazol-2-ylQ709 —CH₃ 5-(2,4-difluorophenyl)thiazol-2-yl Q710 —CH₃5-(3-methoxybenzyl)thiazol-2-yl Q711 —CH₃4-(3-methoxyphenyl)thiazol-2-yl Q712 —CH₃ 4-(4-fluorophenyl)thiazol-2-ylQ713 —CH₂CH₃ 4-(methoxycarbonyl)thiazol-5-yl Q714 —CH₂CH₃4-[(2-methoxy-2- oxoethyl)carbamoyl]thiazol-5-yl Q715 —CH₂CH₃5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3- yl]oxazol-2-yl Q716 —CH₂CH₃5-(2-methoxyphenyl)oxazol-2-yl Q717 —CH₂CH₃5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl Q718 —CH₂CH₃5-[4-(methylcarboxy)phenyl]oxazol-2-yl Q719 —CH₂CH₃5-(3-methoxybenzyl)oxazol-2-yl Q720 —CH₂CH₃ 5-(4-phenyl)oxazol-2-yl Q721—CH₂CH₃ 5-(2-methoxyphenyl)thiazol-2-yl Q722 —CH₂CH₃5-(3-methoxyphenyl)thiazol-2-yl Q723 —CH₂CH₃5-(4-fluorophenyl)thiazol-2-yl Q724 —CH₂CH₃5-(2,4-difluorophenyl)thiazol-2-yl Q725 —CH₂CH₃5-(3-methoxybenzyl)thiazol-2-yl Q726 —CH₂CH₃4-(3-methoxyphenyl)thiazol-2-yl Q727 —CH₂CH₃4-(4-fluorophenyl)thiazol-2-yl Q728 cyclopropyl4-(methoxycarbonyl)thiazol-5-yl Q729 cyclopropyl 4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl Q730 cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3- yl]oxazol-2-yl Q731cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl Q732 cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl Q733cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl Q734 cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl Q735 cyclopropyl 5-(4-phenyl)oxazol-2-ylQ736 cyclopropyl 5-(2-methoxyphenyl)thiazol-2-yl Q737 cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl Q738 cyclopropyl5-(4-fluorophenyl)thiazol-2-yl Q739 cyclopropyl5-(2,4-difluorophenyl)thiazol-2-yl Q740 cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl Q741 cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl Q742 cyclopropyl4-(4-fluorophenyl)thiazol-2-yl

Compounds according to the first aspect of Category IX which comprise asubstituted or unsubstituted thiazol-4-yl unit for R¹ can be prepared bythe procedure outlined in Scheme XVII and described below in Example 18.

EXAMPLE 18(S)-4-(2-(2-Phenylthiazol-4-yl)2-(4-(methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylsulfamicacid (45)

Preparation of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanaminehydrobromide salt (42): A mixture of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (1.62 g, 4.17mmol) and thiobenzamide (0.63 g, 4.60 mmol) in CH₃CN (5 mL) is refluxedfor 24 hours. The reaction mixture is cooled to room temperature anddiethyl ether (50 mL) is added to the solution. The precipitate whichforms is collected by filtration. The solid is dried under vacuum toafford 1.2 g (67% yield) of the desired product. LC/MS ESI+326 (M+1).

Preparation of(S)-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole (43):To a solution of(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromidesalt, 42, (726 mg, 1.79 mmol) and CaCO₃ (716 mg, 7.16 mmol) in H₂O (2mL) is added CCl₄ (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol).The reaction is stirred at room temperature for 18 hours then dilutedwith CH₂Cl₂ and water. The layers are separated and the aqueous layerextracted with CH₂Cl₂. The combined organic layers are washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to a residue which ispurified over silica (CH₂Cl₂) to afford 480 mg (73%) of the desiredproduct as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, J=8.7 Hz,2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 7.15(d, J=0.9 Hz, 1H), 5.40-5.95 (m, 1H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H),3.46 (dd, J=13.8 and 6.0 Hz).

Preparation of (S)-methyl5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)-ethylamino]thiazole-4-carboxylate(44): To a suspension of potassium tert-butoxide (89 mg, 0.75 mmol) inTHF (3 mL) is added methyl isocyanoacetate (65 μL, 0.68 mmol) followedby (S)-2-phenyl-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)thiazole, 43,(250 mg, 0.68 mmol). The reaction mixture is stirred at room temperaturefor 2 hours then poured into sat. NaHCO₃. The mixture is extracted withEtOAc (3× 25 mL) and the combined organic layers are washed with brineand dried (Na₂SO₄) and concentrated in vacuo. The crude residue ispurified over silica to afford 323 mg (— 100% yield) of the desiredproduct as a slightly yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.09-8.13(m, 2H), 7.95-7 98 (m, 3H), 7.84 (d, J=1.2 Hz, 1H), 7.44-7.50 (m, 3H),7.28-7.31(m, 2H), 7.96 (d, J=0.6 Hz, 1H), 4.71-4.78(m, 1H), 3.92 (s,3H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.45 (dd, J=13.8 and 6.0 Hz, 1H).

Preparation of(S)-4-(2-(2-phenylthiazol-4-yl)244-(methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylsulfamicacid (45): (S)-methyl5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)-ethylamino]thiazole-4-carboxylate,44, (323 mg, 0.68 mmol) and tin (II) chloride (612 mg, 2.72 mmol) aredissolved in EtOH and the solution is brought to reflux. The solvent isremoved in vacuo and the resulting residue is dissolved in EtOAc. Asaturated solution of NaHCO₃ is added and the solution is stirred 1hour. The organic layer is separated and the aqueous layer extractedtwice with EtOAc. The combined organic layers are dried (Na₂SO₄),filtered and concentrated to a residue which is dissolved in pyridine(10 mL) and treated with SO₃-pyridine (130 mg, 0.82 mmol). The reactionis stirred at room temperature for 5 minutes after which a 7% solutionof NH₄OH is added. The mixture is then concentrated and the resultingresidue is purified by reverse phase chromatography to afford 0.071 g ofthe desired product as the ammonium salt ¹H NMR (300 MHz, MeOH-d₄) δ7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H), 7.22 (s, 1H), 7.03-7.13 (m, 4H),4.74 (t, J=6.6 Hz, 1H), 3.88 (s, 3H), 3.28-3.42 (m, 2H).

Compounds according to the first aspect of Category IX which comprise asubstituted or unsubstituted thiazol-2-yl unit for R¹ can be prepared bythe procedure outlined in Scheme XVIII and described herein below inExample 19. Intermediate 46 can be prepared according to Scheme II andExample 2 by substituting cyclopropane-carbothioic acid amide forthiophen-2-carbothioic acid amide.

EXAMPLE 194-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)thiazol-2-ylamino]ethyl}phenylsulfamicacid (50)

Preparation of(S)-1-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea(47): To a solution of(S)-1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethan-aminehydrobromide hydrobromide salt, 32, (4.04 g, 10.9 mmol) and CaCO₃ (2.18g, 21.8 mmol) in CCl₄/water (25 mL/20 mL) is added thiophosgene (1.5 g,13.1 mmol). The reaction is stirred at room temperature for 18 hoursthen diluted with CH₂Cl₂ and water. The layers are separated and theaqueous layer extracted with CH₂Cl₂. The combined organic layers arewashed with brine, dried (Na₂SO₄) and concentrated in vacuo to a residuewhich is subsequently treated with ammonia (0.5M in 1,4-dioxane, 120 mL)which is purified over silica to afford 2.90 g of the desired product asa red-brown solid. LC/MS ESI−347 (M−1).

Preparation of(S)-4-(3-methoxybenzyl)-N-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)thiazol-2-amine(48):(S)-1-(1-(2-Cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea,47, (350 mg, 1.00 mmol) and 2-bromo-3′-methoxy-acetophenone (253 mg,1.10 mmol) are combined in 3 mL CH₃CN and heated to reflux for 24 hours.The mixture is concentrated and chromatographed to afford 0.172 g of theproduct as a yellow solid. LC/MS ESI+479 (M+1).

Preparation of4-{(S)-2-(2-cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)-thiazol-2-ylamino]ethyl}phenylsulfamicacid (49):(S)-4-(3-methoxybenzyl)-N-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)thiazol-2-amine,48, (0.172 g) is dissolved in 10 mL MeOH. A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere for 18 hours. The reaction mixture is filtered through a bedof CELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in 5 mL pyridine and treated with SO₃-pyridine (114mg). The reaction is stirred at room temperature for 5 minutes afterwhich 10 mL of a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse-phasechromatography to afford 0.033 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84-6.80(m, 2H), 5.02 (t, 1H, J=6.9 Hz), 3.82 (s, 1H), 3.18 (q, 2H, J=7.1 Hz),2.36 (q, 1H, J=4.6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).

The following are non-limiting examples of compounds encompassed withinthe first aspect of Category IX.

(S)-4-(2-(4-((2-Methoxy-2-oxoethyl)carbamoyl)thiazole-5-ylamino)2-(2-ethylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.91 (s, 1H), 7.08-7.10 (m, 3H), 6.99(d, J=8.7 Hz, 2H), 4.58 (t, J=6.9 Hz, 1H), 4.11 (d, J=2.7 Hz, 2H), 3.78(s, 3H), 3.14-3.28 (m, 2H), 3.06 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz,3H).

(S)-4-(2-{5-[1-N-(2-Methoxy-2-oxoethylcarbamoyl)-1-H-indol-3-yl]oxazol-2-ylamino}-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.63 (d, J=7.8 Hz, 1H), 7.37 (s, 1H),7.18-7.29 (m, 4H), 7.02-7.16 (m, 4H), 6.85 (s, 1H), 5.04-5.09 (m, 1H),4.85 (s, 3H), 3.27 (dd, J=13.5 and 8.1 Hz, 1H), 3.10 (m, J=13.5 and 8.1Hz, 1H), 2.69 (s, 3H).

4-((S)-2-(5-(2-Methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.52 (dd, J=7.5 and 1.2 Hz, 1H),6.95-7.24 (m, 10H), 5.04-5.09 (m, 1H), 3.92 (s, 3H), 3.26 (dd, J=13.8and 8.4 Hz, 1H), 3.10 (dd, J=13.8 and 8.4 Hz, 1H), 2.72 (s, 3H).

4-((S)-2-(5-((S)-1-(tert-Butoxycarbonyl)-2-phenylethyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.03-7.27 (m, 10 H), 6.50 (s, 1H),4.95-5.00 (m, 1H), 4.76 (t, J=6.9 Hz, 1H), 3.22 (dd, J=14.1 and 6.9 Hz,1H), 3.00-3.10 (m, 2H), 2.90 (dd, J=14.1 and 6.9 Hz, 1H), 2.72 (s, 3H),1.37 (s, 9H).

(S)-{4-{2-[5-(4-Methoxycarbonyl)phenyl]oxazol-2-ylamino}-2-(2-methylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.99 (d, J=7.5 Hz, 2H), 7.56 — 7.59(m, 2H), 7.23-7.24 (m, 1H), 7.08-7.14 (m, 4H), 6.83 (d, J=10.2 Hz, 1H),5.08 (t, J=6.0 Hz, 1H), 3.91 (s, 3H), 3.25-3.35 (m, 1H), 3.09-3.13 (m,1H), 2.73 (s, 3H).

(S)-4-(2-(5-(3-Methoxybenzyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.03 — 7.28 (m, 8H), 6.79-6.83 (m,1H), 5.70 (s, 1H), 4.99-5.06 (m, 2H), 4.41 (d, J=2.1 Hz, 2H), 3.80 (s,3H), 3.27-3.37 (m, 1H), 3.03-3.15 (m, 1H), 2.71 (s, 3H).

(S)-4-(2-(2-Methylthiazole-4-yl)2-(5-phenyloxazole-2-ylamino)ethyl)phenyl-sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.45 (d, J=8.7 Hz, 2H), 7.33 (t, J=7.8Hz, 2H), 7.18-7.22 (m, 1H), 7.10-7.14 (m, 6H), 7.04 (s, 1H), 5.04-5.09(m, 1H), 3.26 (dd, J=13.8 and 6.3 Hz, 1H), 3.10 (dd, J=13.8 and 6.3 Hz,1H), 2.70 (s, 3H).

4-((S)-2-(2-Cyclopropylthiazol-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2-ylamino)-ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84-6.80(m, 2H), 5.02 (t, 1H, J=6.9 Hz), 3.82 (s, 1H), 3.18 (q, 2H, J=7.1 Hz),2.36 (q, 1H, J=4.6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).

(S)-4-(2-(2-cyclopropylthiazol-4-yl)-2-(4-(4-fluorophenyl)thiazol-2-ylamino)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.79-7.74 (m, 2H), 7.14-7.03 (m, 7H), 7.21 (s,1H), 6.79 (s, 1H), 5.08 (t, 1H, J=6.6 Hz), 3.29-3.12 (m, 2H), 2.40 (q,2.40, J=5.1 Hz), 1.23-1.18 (m, 2H), 1.08-1.02 (m, 2H).

4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2-ylamino)-ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.89-7.87 (d, 1H, J=7.6 Hz), 7.28 (t, 1H, J=7.0Hz), 7.10-6.96 (m, 8H), 5.03 (t, 1H, J=6.9 Hz), 3.90 (s, 1H), 3.19 (q,2H, J=6.6 Hz), 2.38 (q, 1H, J=4.8 Hz), 1.21-1.14 (m, 2H), 1.06-1.00 (m,2H).

4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2,4-difluorophenyl)thiazol-2-ylamino)-ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.06-8.02 (q, 2H, J=6.9 Hz), 7.12-6.95 (m, 7H),6.88 (s, 1H), 5.11 (t, 1H, J=6.9 Hz), 3.22-3.15 (m, 2H), 2.38 (q, 1H,J=4.8 Hz), 1.22-1.15 (m, 2H), 1.06-1.02 (m, 2H).

(S)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylthiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.22-7.17 (m, 3H), 7.09-6.97 (m, 5H), 6.78-6.66(m, 3H), 3.77 (s, 2H), 3.75 (s, 3H), 3.20-3.07 (m, 2H), 2.35 (q, 1H,J=4.8 Hz), 1.19-1.13 (m, 2H), 1.03-1.00 (m, 2H).

(S)-{5-[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylamino]-2-methyl-2H-[1,2,4]triazole-3-yl}carbamicacid methyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 6.97-7.08 (m, 5H), 3.71(s, 3H), 3.51 (s, 3H), 3.15 (dd, J=13.5 and 6.3 Hz, 1H), 3.02-3.07 (m,3H), 1.40 (t, J=6.6 Hz, 3H).

The second aspect of Category IX of the present disclosure relates tocompounds having the formula:

wherein R¹ is a substituted or unsubstituted heteroaryl and R⁴ issubstituted or unsubstituted phenyl and substituted or unsubstitutedheteroaryl as further described below in Table

XVIII.

TABLE XVIII No. R⁴ R¹ R743 phenyl 4-(methoxycarbonyl)thiazol-5-yl R744phenyl 4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol- 5-yl R745 phenyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3- yl]oxazol-2-yl R746 phenyl5-(2-methoxyphenyl)oxazol-2-yl R747 phenyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl R748 phenyl5-[4-(methylcarboxy)phenyl]oxazol-2-yl R749 phenyl5-(3-methoxybenzyl)oxazol-2-yl R750 phenyl 5-(4-phenyl)oxazol-2-yl R751phenyl 5-(2-methoxyphenyl)thiazol-2-yl R752 phenyl5-(3-methoxyphenyl)thiazol-2-yl R753 phenyl5-(4-fluorophenyl)thiazol-2-yl R754 phenyl5-(2,4-difluorophenyl)thiazol-2-yl R755 phenyl5-(3-methoxybenzyl)thiazol-2-yl R756 phenyl4-(3-methoxyphenyl)thiazol-2-yl R757 phenyl4-(4-fluorophenyl)thiazol-2-yl R758 thiophen-2-yl4-(methoxycarbonyl)thiazol-5-yl R759 thiophen-2-yl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol- 5-yl R760 thiophen-2-yl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol- 3-yl]oxazol-2-yl R761thiophen-2-yl 5-(2-methoxyphenyl)oxazol-2-yl R762 thiophen-2-yl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl R763thiophen-2-yl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl R764 thiophen-2-yl5-(3-methoxybenzyl)oxazol-2-yl R765 thiophen-2-yl5-(4-phenyl)oxazol-2-yl R766 thiophen-2-yl5-(2-methoxyphenyl)thiazol-2-yl R767 thiophen-2-yl5-(3-methoxyphenyl)thiazol-2-yl R768 thiophen-2-yl5-(4-fluorophenyl)thiazol-2-yl R769 thiophen-2-yl5-(2,4-difluorophenyl)thiazol-2-yl R770 thiophen-2-yl5-(3-methoxybenzyl)thiazol-2-yl R771 thiophen-2-yl4-(3-methoxyphenyl)thiazol-2-yl R772 thiophen-2-yl4-(4-fluorophenyl)thiazol-2-yl R773 cyclopropyl4-(methoxycarbonyl)thiazol-5-yl R774 cyclopropyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol- 5-yl R775 cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3- yl]oxazol-2-yl R776cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl R777 cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl R778cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl R779 cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl R780 cyclopropyl 5-(4-phenyl)oxazol-2-ylR781 cyclopropyl 5-(2-methoxyphenyl)thiazol-2-yl R782 cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl R783 cyclopropyl5-(4-fluorophenyl)thiazol-2-yl R784 cyclopropyl5-(2,4-difluorophenyl)thiazol-2-yl R785 cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl R786 cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl R787 cyclopropyl4-(4-fluorophenyl)thiazol-2-yl

Compounds according to the second aspect of Category IX which comprise asubstituted or unsubstituted thiazol-4-yl unit for R¹ can be prepared bythe procedure outlined in Schemes XIX, XX, and XXI, and described belowin Examples 20, 21, and 22.

EXAMPLE 20(S)-4-(2-(5-Methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)phenylsulfamicacid (55)

Preparation of [3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester (50): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g,4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). Thereaction mixture is stirred at 0° C. for 20 minutes then filtered. Thefiltrate is treated with an ether solution of diazomethane (˜16 mmol) at0° C. The reaction mixture is stirred at room temperature for 3 hoursand concentrated. The residue is dissolved in EtOAc and washedsuccessively with water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue is purified over silica(hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product asa slightly yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J=8.7 Hz,2H), 7.39 (d, J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49(s, 1H), 3.25 (dd, J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz,1H), 1.41 (s, 9H).

Preparation of [3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester (51): To a 0° C. solution of[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester,50, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr(0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0° C. for 1.5hours and quenched at 0° C. with saturated aqueous Na₂CO₃. The mixtureis extracted with EtOAc (3×25 mL) and the combined organic extracts arewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo toafford 0.400 g of the desired product that is used in the next stepwithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 8.20 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4- yl)ethanaminehydrobromide salt (52): A mixture of[3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl]-carbamic acid tert-butylester, 51, (1.62 g, 4.17 mmol) and benzothioamide (0.630 g, 4.59 mmol),in CH₃CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooledto room temperature and diethyl ether (50 mL) is added to the solutionand the precipitate that forms is collected by filtration. The solid isdried under vacuum to afford 1.059 g (63%) of the desired product.ESI+MS 326 (M+1).

Preparation of(S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole (53):To a solution of (S)-2(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanaminehydrobromide salt, 52, (2.03 g, 5 mmol) and CaCO₃ (1 g, 10 mmol) inCCl₄/water (10:7.5 mL) is added thiophosgene (0.46 mL, 6 mmol). Thereaction is stirred at room temperature for 18 hours then diluted withCH₂Cl₂ and water. The layers are separated and the aqueous layerextracted with CH₂Cl₂. The combined organic layers are washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to a residue that ispurified over silica (CH₂Cl₂) to afford 1.71 g (93% yield) of thedesired product. ESI+MS 368 (M+1).

Preparation of(S)-5-methyl-N-[2-(4-nitrophenyl)-142-phenylthiazol-4-yl)ethyl]-1,3,4-thiadiazol-2-amine(54): A solution of(S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole, 53,(332 mg, 0.876 mmol) and acetic hydrazide (65 mg, 0.876 mmol) in EtOH (5mL) is refluxed for 2 hours. The solvent is removed under reducedpressure, the residue is dissolved in POCl₃ (3 mL) and the resultingsolution is stirred at room temperature for 18 hours after which thesolution is heated to 50° C. for 2 hours. The solvent is removed invacuo and the residue is dissolved in EtOAc (40 mL) and the resultingsolution is treated with 1N NaOH until the pH remains approximately 8.The solution is extracted with EtOAc. The combined aqueous layers arewashed with EtOAc, the organic layers combined, washed with brine, driedover MgSO₄, filtered, and concentrated in vacuo to afford 0.345 g (93%yield) of the desired product as a yellow solid. ¹H NMR (CDCl₃) 8.09 (d,J=8.4 Hz, 2H), 7.91 (m, 2H), 7.46 (m, 4H), 7.44 (s, 1H), 5.23 (m, 1H),3.59 (m, 2H), 2.49 (s, 3H). ESI+MS 424 (M+1).

Preparation of(S)-4-[2-(5-methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenylsulfamicacid (55): (S)-5-Methyl-N-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]-1,3,4-thiadiazol-2-amine,54, (0.404 g, 0.954 mmol) is dissolved in MeOH (5 mL). Pd/C (50 mg, 10%w/w) is added and the mixture is stirred under a hydrogen atmosphereuntil the reaction is judged to be complete. The reaction mixture isfiltered through a bed of CELITE™ and the solvent removed under reducedpressure. The crude product is dissolved in pyridine (4 mL) and treatedwith SO₃-pyridine (0.304 g, 1.91 mmol). The reaction is stirred at roomtemperature for 5 minutes after which a 7% solution of NH₄OH (50 mL) isadded. The mixture is then concentrated and the resulting residue ispurified by reverse phase preparative HPLC to afford 0.052 g (11% yield)of the desired product as the ammonium salt. ¹H NMR (CD₃OD): δ 8.00-7.97(m, 2H), 7.51-7.47 (m, 3H), 7.23 (s, 1H), 7.11-7.04 (q, 4H, J=9.0 Hz),5.18 (t, 1H, J=7.2 Hz), 3.34-3.22 (m, 2H), 2.50 (s, 3H). ESI−MS 472(M−1).

EXAMPLE 214-{(S)-2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (58)

Preparation of(S)-1-[1-(thiophen-2-ylthiazol-4-yl)-2-(4-nitrophenyl)ethyl]-thiourea(56): To a solution of(S)-2-(4-nitrophenyl)-1-(thiophen-2-ylthiazol-4-yl)ethanaminehydrobromide salt, 8, (1.23 g, 2.98 mmol) and CaCO₃ (0.597 g, 5.96 mmol)in CCl₄/water (10 mL/5 mL) is added thiophosgene (0.412 g, 3.58 mmol).The reaction is stirred at room temperature for 18 hours then dilutedwith CH₂Cl₂ and water. The layers are separated and the aqueous layerextracted with CH₂Cl₂. The combined organic layers are washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to a residue which issubsequently treated with ammonia (0.5M in 1,4-dioxane, 29.4 mL, 14.7mmol) which is purified over silica to afford 0.490 g of the desiredproduct as a red-brown solid. ESI+MS 399 (M+1).

Preparation of4-(2-methoxyphenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}thiazol-2-amine (57):(S)-1-[1-(thiophen-2-ylthiazol-4-yl)-2-(4-nitrophenyl)ethyl]-thiourea,56, (265 mg, 0.679 mmol) is treated with bromo-2′-methoxyacetophenone(171 mg, 0.746 mmol) to afford 0.221 g of the product as a yellow solid.ESI+MS 521 (M+1).

Preparation on4-{(S)-2-14-(2-methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (58):4-(2-methoxyphenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}thiazol-2-amine,57, (0.229 g) is dissolved in 12 mL MeOH. A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere for 18 hours. The reaction mixture is filtered through a bedof CELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in 6 mL pyridine and treated with SO₃-pyridine (140mg). The reaction is stirred at room temperature for 5 minutes afterwhich 10 mL of a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse-phasechromatography to afford 0.033 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD): δ 7.96-7.93 (m, 1H), 7.60-7.55 (m, 2H), 7.29-7.23(m, 1H), 7.18-6.95 (m, 9H), 5.15 (t, 1H, J=6.9 Hz), 3.90 (s, 3H),3.35-3.24 (m, 2H).

Compounds according to the second aspect of Category IX which comprise asubstituted or unsubstituted oxazol-2-yl unit for R¹ can be prepared bythe procedure outlined in Scheme XXI and described herein below inExample 22. Intermediate 39 can be prepared according to Scheme XVII andExample 18.

EXAMPLE 224-{(S)-2-[5-(3-Methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamicacid (61)

Preparation of[5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethyl]amine (60): A mixture of(S)-4-(isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole, 53, (300mg, 0.81 mmol), 1-azido-1-(3-methoxyphenyl)ethanone (382 mg, 2.0 mmol)and PPh₃ (0.8 g, polymer bound, ˜3 mmol/g) in dioxane (6 mL) is heatedat 90° C. for 20 minutes. The reaction solution is cooled to roomtemperature and the solvent removed in vacuo and the resulting residueis purified over silica to afford 300 mg (74% yield) of the desiredproduct as a yellow solid. ¹H NMR (300 MHz, MeOH-d₄) δ 8.02 (d, J=7.2Hz, 2H), 7.92-7.99 (m, 2H), 7.42-7.47 (m, 3H), 7.22-7.27 (m, 3H),6.69-7.03 (m, 4H), 6.75-6.78 (m, 1H), 5.26 (t, J=6.3 Hz, 1H), 3.83 (s,4H), 3.42-3.45 (m, 2H).

Preparation of4-{(S)-2-[5-(3-methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamicacid (61):[5-(3-methoxyphenyeoxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethyl]amine, 60, (300 mg, 0.60 mmol) is dissolved in MeOH (15 mL). Acatalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 18 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (10 mL) and treatedwith SO₃-pyridine (190 mg, 1.2 mmol). The reaction is stirred at roomtemperature for 5 minutes after which a 7% solution of NH₄OH is added.The mixture is then concentrated and the resulting residue is purifiedby reverse-phase chromatography to afford 0.042 g of the desired productas the ammonium salt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.99 d, J=7.5 Hz, 2H),7.46 — 7.50 (m, 3H),7.23-7.29 (m, 3H), 7.04-7.12 (m, 6H), 6.78 (dd,J=8.4 and 2.4 Hz, 1H), 5.16 (t, J=6.6 Hz, 1H), 3.81 (s, 3H), 3.29-3.39(m, 1H), 3.17 (dd, J=13.8 and 8.1 Hz, 1H).

The following are non-limiting examples of the second aspect of CategoryIX of the present disclosure.

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.97-7.94 (m, 2H), 7.73-7.70 (m, 2H), 7.44-7.39(m, 6H), 7.25 (s, 1H), 7.12 (s, 4H), 5.29 (t, 1H, J=6.9 Hz), 3.35-3.26(m, 2H).

4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.59-7.54 (m, 2H), 7.17-7.03 (m, 6H), 5.13 (t,1H, J=7.2 Hz), 3.32-3.13 (m, 2H), 2.81 (t, 2H, J=7.4 Hz), 1.76-1.63 (h,6H, J=7.4 Hz), 0.97 (t, 3H, J=7.3 Hz).

4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ (m, 2H), 7.49-7.45 (m, 2H), 7.26-7.16 (m, 5H),7.05-6.94 (m, 6H), 5.04 (t, 1H, J=7.1 Hz), 4.07 (s, 2H), 3.22-3.04 (m,2H).

4-((S)-2-(5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.08-8.05 (m, 1H), 7.89-7.80 (m, 2H), 7.55-7.43(m, 6H), 7.11-7.00 (m, 6H), 5.08 (t, 1H, J=7.1 Hz), 4.63 (s, 2H),3.26-3.08 (m, 2H).

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.48-7.44 (m, 2H), 7.03-6.92 (m, 6H), 5.02 (t,1H, J=7.2 Hz), 4.30 (s, 2H), 3.55 (s, 3H), 3.22-3.02 (m, 2H).

4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.60-7.56 (m, 2H), 7.19 (s, 1H), 7.15-7.12 (m,2H), 7.09-7.03 (q, 4H, J=8.7 Hz), 5.14 (t, 1H, J=7.2 Hz), 4.28 (s, 2H),3.33-3.14 (m, 2H), 2.67 (s, 3H).

4-{(S)-2-[4-(2,4-Difluorophenyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.06-8.02 (q, 1H, J=6.8 Hz), 7.59-7.54 (m, 2H),7.16-7.08 (m, 6H), 7.01-6.88 (m, 4H), 5.20 (t, 1H, J=7.0 Hz), 3.36-3.17(m, 2H).

(S)-4-{2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.02-7.99 (m, 2H), 7.54-7.45 (m, 4H), 7.26 (s,1H), 7.08 (s, 4H), 5.26 (t, 1H, J=6.9 Hz), 4.35-4.28 (q, 2H, J=6.9 Hz),3.38-3.18 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).

(S)-4-{2-[4-(2-Ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.96 (m, 2H), 7.50-7.46 (m, 3H), 7.21 (s, 1H),7.10-7.04 (m, 4H), 6.37 (s, 1H), 5.09 (t, 1H, J=6.9 Hz), 4.17-4.10 (q,2H, J=7.1 Hz), 3.54 (s, 2H), 3.35-3.14 (m, 2H), 1.22 (t, 3H, J=7.1 Hz).

(S)-4-{2-[4-(4-acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.11 (m, 2H), 7.82-7.80 (m, 2H), 7.71-7.61 (m,6H), 7.40 (s, 1H), 7.23 (s, 4H), 5.32 (t, 1H, J=7.0 Hz), 3.51-3.35 (m,2H), 2.28 (s, 3H).

(S)-4-[2-(4-phenylthiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.03-7.99 (m, 2H), 7.75-7.72 (d, 2H, J=8.4 Hz),7.53-7.48 (m, 3H), 7.42 (m, 4H), 7.12 (s, 4H), 6.86 (s, 1H), 5.23 (t,1H, J=7.2 Hz), 3.40-3.27 (m, 2H).

(S)-4-{2-[4-(4-(methoxycarbonyephenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.04-8.00 (m, 4H), 7.92-7.89 (d, 2H, J=9.0 Hz),7.53-7.49 (m, 3H), 7.30 (s, 1H), 7.15 (s, 4H), 7.05 (s, 1H), 5.28 (t,1H, J=6.9 Hz), 3.93 (s, 3H), 3.35-3.24 (m, 2H).

4-{(S)-2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.43-7.38 (m, 2H), 7.26 (s, 1H), 7.00-6.94 (m,3H), 6.89 (s, 4H), 5.02 (t, 1H, J=7.0 Hz), 4.16-4.09 (q, 2H, J=7.1 Hz),3.14-2.94 (m, 2H), 1.17 (t, 3H, J=7.1 Hz).

(S)-4-[2-(4-(Methoxycarbonyl)thiazol-5-ylamino)-2-(2-phenylthiazole-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H),7.22 (s, 1H), 7.03-7.13 (m, 4H), 4.74 (t, J=6.6 Hz, 1H), 3.88 (s, 3H),3.28-3.42 (m, 2H).

(S)-4-[2-(5-Phenyloxazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]-phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.94-7.96 (m, 2H), 7.45-7.49 (m, 5H),7.32 (t, J=7.8 Hz, 2H), 7.12 (s, 1H), 7.19 (t, J=7.2 Hz, 1H), 7.12 (s,4H), 7.05 (s, 1H), 5.15 (t, J=6.4 Hz, 1H), 3.34 (dd, J=14.1 and 8.4 Hz,1H), 3.18 (dd, J=14.1 and 8.4 Hz, 1H).

(S)-4-{2-[5-(4-Acetamidophenyl)oxazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.92-7.94 (m, 2H), 7.55-7.58 (m, 2H),7.39-7.50 (m, 5H), 7.26 (s, 1H), 7.12 (s, 4H), 7.02 (s, 1H0), 5.14 (t,J=7.8 Hz, 1H), 3.13-3.38 (m, 2H), 2.11 (s, 3H).

4-((S)-2-(5-(2,4-Difluorophenyl)oxazole-2-ylamino)-2-(2-phenylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.97-7.99 (m, 2H), 7.54-7.62 (m, 1H),7.45-7.50 (m, 3H), 7.28 (s, 1H), 7.12 (s, 4H), 6.97-7.06 (m, 3H),5.15-5.20 (m, 1H), 3.28-3.40 (m, 1H), 3.20 (dd, J=13.8 and 8.4 Hz, 1H).

4-{(S)-2-[5-(3-Methoxyphenyl)oxazol-2-ylamino]-2-[(2-thiophen-2-yl)thiazole-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.55 — 7.60 (m, 2H), 7.26 (t, J=8.1Hz, 1H), 7.21 (s, 1H), 7.04-7.15 (m, 8H), 6.77-6.81 (m, 1H), 5.10 (t,J=6.3 Hz, 1H), 3.81 (s, 3H), 3.29-3.36(m, 1H), 3.15 (dd, J=14.1 and 8.4Hz, 1H).

(S)-4-[2-(4,6-Dimethylpyrimidin-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.00-7.10 (m, 5H), 6.44 (s, 1H), 5.50(t, J=7.2 Hz, 1H), 3.04-3.22 (m, 2H), 2.73 (s, 3H), 2.27 (s, 6H).

(S)-4-[2-(4-Hydroxy-6-methylpyrimidine-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d4) δ 7.44 (d, J=8.4 Hz,2H), 6.97-7.10 (m,4H), 5.61 (s, 1H), 5.40 — 5.49 (m, 1H), 3.10 — 3.22 (m, 2H), 2.73 (s,3H), 2.13 (s, 3H).

The first aspect of Category X of the present disclosure relates tocompounds having the formula:

wherein R¹ is heteroaryl and R⁴ is further described below in Table XIX.

TABLE XIX No. R⁴ R¹ S788 phenyl 4-(methoxycarbonyl)thiazol-5-yl S789phenyl 4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol- 5-yl S790 phenyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3- yl]oxazol-2-yl S791 phenyl5-(2-methoxyphenyl)oxazol-2-yl S792 phenyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl S793 phenyl5-[4-(methylcarboxy)phenyl]oxazol-2-yl S794 phenyl5-(3-methoxybenzyl)oxazol-2-yl S795 phenyl 5-(4-phenyl)oxazol-2-yl S796phenyl 5-(2-methoxyphenyl)thiazol-2-yl S797 phenyl5-(3-methoxyphenyl)thiazol-2-yl S798 phenyl5-(4-fluorophenyl)thiazol-2-yl S799 phenyl5-(2,4-difluorophenyl)thiazol-2-yl S800 phenyl5-(3-methoxybenzyl)thiazol-2-yl S801 phenyl4-(3-methoxyphenyl)thiazol-2-yl S802 phenyl4-(4-fluorophenyl)thiazol-2-yl S803 thiophen-2-yl4-(methoxycarbonyl)thiazol-5-yl S804 thiophen-2-yl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol- 5-yl S805 thiophen-2-yl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3- yl]oxazol-2-yl S806thiophen-2-yl 5-(2-methoxyphenyl)oxazol-2-yl S807 thiophen-2-yl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl S808thiophen-2-yl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl S809 thiophen-2-yl5-(3-methoxybenzyl)oxazol-2-yl S810 thiophen-2-yl5-(4-phenyl)oxazol-2-yl S811 thiophen-2-yl5-(2-methoxyphenyl)thiazol-2-yl S812 thiophen-2-yl5-(3-methoxyphenyl)thiazol-2-yl S813 thiophen-2-yl5-(4-fluorophenyl)thiazol-2-yl S814 thiophen-2-yl5-(2,4-difluorophenyl)thiazol-2-yl S815 thiophen-2-yl5-(3-methoxybenzyl)thiazol-2-yl S816 thiophen-2-yl4-(3-methoxyphenyl)thiazol-2-yl S817 thiophen-2-yl4-(4-fluorophenyl)thiazol-2-yl S818 cyclopropyl4-(methoxycarbonyl)thiazol-5-yl S819 cyclopropyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol- 5-yl S820 cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3- yl]oxazol-2-yl S821cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl S822 cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2- phenylethyl]oxazol-2-yl S823cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl S824 cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl S825 cyclopropyl 5-(4-phenyl)oxazol-2-ylS826 cyclopropyl 5-(2-methoxyphenyl)thiazol-2-yl S827 cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl S828 cyclopropyl5-(4-fluorophenyl)thiazol-2-yl S829 cyclopropyl5-(2,4-difluorophenyl)thiazol-2-yl S830 cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl S831 cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl S832 cyclopropyl4-(4-fluorophenyl)thiazol-2-yl

Compounds according to the first aspect of Category X can be prepared bythe procedure outlined in Scheme XXII and described below in Example 23.

EXAMPLE 234-((S)-2-(2-(3-Chlorophenyl)acetamido)-2-(2-(thiophen-2-yl)oxazol-4-yl)ethyl)phenylsulfamicacid (64)

Preparation of(S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)oxazol-4-yl]ethanaminehydrobromide salt (62): A mixture of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (38.7 g, 100mmol), and thiophen-2-carboxamide (14 g, 110 mmol) (available from AlfaAesar) in CH₃CN (500 mL) is refluxed for 5 hours. The reaction mixtureis cooled to room temperature and diethyl ether (200 mL) is added to thesolution. The precipitate which forms is collected by filtration. Thesolid is dried under vacuum to afford the desired product which can beused for the next step without purification.

Preparation of2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)oxazol-4-yl]ethyl}acetamide(63): To a solution of(S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)oxazol-4-yl]ethanamine HBr, 47,(3.15 g, 10 mmol) 3-chlorophenyl-acetic acid (1.70 g, 10 mmol) and1-hydroxybenzotriazole (HOBt) (0.70 g, 5.0 mmol) in DMF (50 mL) at 0°C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.90g, 10 mmol) followed by triethylamine (4.2 mL, 30 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford the desired product which is used without furtherpurification.

Preparation of—((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophen-2-yl)oxazol-4-yl)ethyl)phenylsulfamicacid (64):2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)oxazol-4-yl]ethyl}acetamide,63, (3 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10%w/w) is added and the mixture is stirred under a hydrogen atmosphere 18hours. The reaction mixture is filtered through a bed of CELITE™ and thesolvent is removed under reduced pressure. The crude product isdissolved in pyridine (12 mL) and treated with SO₃-pyridine (0.157 g).The reaction is stirred at room temperature for 5 minutes after which a7% solution of NH₄OH is added. The mixture is then concentrated and theresulting residue can be purified by reverse phase chromatography toafford the desired product as the ammonium salt.

The second aspect of Category X of the present disclosure relates tocompounds having the formula:

wherein R¹ is aryl and R² and R³ are further described herein below inTable XX.

TABLE XX No. R² R³ R¹ T833 methyl hydrogen phenyl T834 methyl hydrogenbenzyl T835 methyl hydrogen 2-fluorophenyl T836 methyl hydrogen3-fluorophenyl T837 methyl hydrogen 4-fluorophenyl T838 methyl hydrogen2-chlorophenyl T839 methyl hydrogen 3-chlorophenyl T840 methyl hydrogen4-chlorophenyl T841 ethyl hydrogen phenyl T842 ethyl hydrogen benzylT843 ethyl hydrogen 2-fluorophenyl T844 ethyl hydrogen 3-fluorophenylT845 ethyl hydrogen 4-fluorophenyl T846 ethyl hydrogen 2-chlorophenylT847 ethyl hydrogen 3-chlorophenyl T848 ethyl hydrogen 4-chlorophenylT849 thien-2-yl hydrogen phenyl T850 thien-2-yl hydrogen benzyl T851thien-2-yl hydrogen 2-fluorophenyl T852 thien-2-yl hydrogen3-fluorophenyl T853 thien-2-yl hydrogen 4-fluorophenyl T854 thien-2-ylhydrogen 2-chlorophenyl T855 thien-2-yl hydrogen 3-chlorophenyl T856thiene-2-yl hydrogen 4-chlorophenyl

Compounds according to the second aspect of Category X can be preparedby the procedure outlined in Scheme XXIII and described below in Example24.

EXAMPLE 24{4-[2-(S)-(4-Ethyloxazol-2-yl)-2-phenylacetylaminoethyl]-phenyl}sulfamicacid (67)

Preparation of (S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyeethanamine(65): A mixture of [1-(S)-carbamoyl-2-(4-nitrophenyeethyl-carbamic acidtert-butyl ester, 1, (10 g, 32.3 mmol) and 1-bromo-2-butanone (90%, 4.1mL, 36 mmol) in CH₃CN (500 mL) is refluxed for 18 hours. The reactionmixture is cooled to room temperature and diethyl ether is added to thesolution and the precipitate which forms is removed by filtration and isused without further purification.

Preparation ofN-[1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide(66): To a solution of(S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine, 65, (2.9 g, 11mmol), phenylacetic acid (1.90 g, 14 mmol) and 1-hydroxybenzotriazole(HOBt) (0.94 g, 7.0 mmol) in DMF (100 mL) at 0° C., is added1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI) (2.68 g, 14 mmol)followed by triethylamine (6.0 mL, 42 mmol). The mixture is stirred at0° C. for 30 minutes then at room temperature overnight. The reactionmixture is diluted with water and extracted with EtOAc. The combinedorganic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO₃, waterand brine, and dried over Na₂SO₄. The solvent is removed in vacuo toafford the desired product which is used without further purification.

Preparation of{4-[2-(S)-(4-ethyloxazol-2-yl)-2-phenylacetylaminoethyl]-phenyl}sulfamicacid (67):N-[1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide,66, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.177 g, 1.23). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH (10 mL) is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford the desired product as the ammonium salt.

Non-limiting examples of the HPTP-β IC₅₀ μM) activity for illustrativecompounds are listed in Table XXI. HPTP-β inhibition can be tested byany method chosen by the formulator, for example, Amarasinge K. K. etal., “Design and Synthesis of Potent, Non-peptidic Inhibitors ofHPTPbeta” Bioorg Med Chem Lett. 2006 August 15;16(16):4252-6. Epub 2006June 12. Erratum in: Bioorg Med Chem Lett. 2008 August 15;18(16):4745.Evidokimov, Artem G [corrected to Evdokimov, Artem G]: PMID: 16759857;and Klopfenstein S. R. et al. “1,2,3,4-Tetrahydroisoquinolinyl SulfamicAcids as Phosphatase PTP1B Inhibitors” Bioorg Med Chem Lett. 2006 Mar15;16(6):1574-8, both of which are incorporated herein by reference intheir entirety.

TABLE XXI HPTP-β No. Compound IC₅₀ μM AA1

0.000157 (S)-{4-[2-(4-Ethylthiazol-2-yl)-2-(phenylacetylamino)ethyl]-phenyl}sulfamic acid AA2

0.004 4-{(S)-2-[(R)-2-(tert-butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acid AA3

0.031 {1-[1-(5-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethyl-carbamoy]-(S)-2- phenylethyl}methyl carbamic acidtert-butyl ester AA4

<5 × 10⁻⁸ {1-[1-(5-phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2- phenylethyl}methyl carbamic acidtert-butyl ester AA5

<5 × 10⁻⁸ 4-{(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido-2-(2-phenylthiazol-4- yl)}phenylsulfamic acid AA6

0.000162 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acidAA7

0.006 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(thiazol-2- yl)ethyl}phenylsulfamic acid AA8

0.001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-methylthiazol-2- yl)ethyl}phenylsulfamic acidAA9

0.0001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-propylthiazol-2- yl)ethyl}phenylsulfamic acidAA10

0.0002 4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acidAA11

0.00001 4-{(S)-2-(4-Cyclopropylthiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acid AA12

<5 × 10⁻⁸ 4-{(S)-2-(4-Cyclohexylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl- propanamido]ethyl}phenylsulfamic acidAA13

0.001 4-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl- propanamido]ethyl}phenylsulfamic acidAA14

0.0001 4-{(S)-2-(4-Ethyl-5-methylthiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino)-3-phenyl- propanamido]ethyl}phenylsulfamic acidAA15

0.0003 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(2,2,2-trifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamic acid AA16

0.00008 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido)-2-[4-(3,3,3-trifluoropropyl)thiazol-2-yl]ethyl}phenylsulfamic acid AA17

0.001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(methoxymethyl)thiazol-2-yl]ethyl}phenylsulfamic acid AA18

0.0002 4-{(S)-2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acidAA19

0.0003 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(5-phenylthiazol-2- yl)ethyl}phenylsulfamic acidAA20

<5 × 10⁻⁸ 4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino)-3-phenyl- propanamido]ethyl}phenylsulfamic acidAA21

<2 × 10⁻⁶ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-phenylthiazol-2- yl)ethyl}phenylsulfamic acidAA22

<5 × 10⁻⁸ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-2-yl)thiazol-2-yl]ethyl}phenylsulfamic acid AA23

0.00009 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamic acid AA24

0.001 4-{(S)-2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamicacid AA25

0.0004 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}phenylsulfamic acid AA26

<5 × 10⁻⁸ 4-{(S)-2-[4-(5-Chlorothiophen-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenyl-sulfamic acidAA27

0.00014 4-{(S)-2-[(S)-2-(Ethoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acidAA28

0.0001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl) ethyl}phenylsulfamic acidAA29

0.001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-methylthiazol-4- yl)ethyl}phenylsulfamic acidAA30

0.0002 4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxy-carbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acid AA31

0.00008 4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid AA32

0.002 4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3 phenylpropanamido]ethyl}phenylsulfamicacid AA33

  7 × 10⁻⁷ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamido]-2-(2-phenylthiazole-4- yl)ethyl}phenylsulfamic acidAA34

  5 × 10⁻⁸ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid AA35

<5 × 10⁻⁸ 4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acidAA36

<5 × 10⁻⁸ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid AA37

0.0004 4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxy-carbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acid AA38

0.003 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(pyrazin-2-yl)thiazol-4- yl]ethyl}phenylsulfamicacid AA39

0.001 4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid AA40

0.0003 4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-yl)ethyl]phenylsulfamic acid AA41

0.00024 4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamic acid AA42

0.006 4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acid AA43

0.028 (S)-4-{2-[2-(tert-Butoxycarbonylamino)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid AA44

0.020 (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonylamino)acetamido]ethyl}phenylsulfamic acid AA45

0.003 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-methylbutanamido]- ethyl}phenylsulfamic acidAA46

0.001 4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acidAA47

0.0003 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-4- methylpentanamido]ethyl}phenylsulfamic acidAA48

0.0003 4-((S)-2-(4-Ethylthiazol-2-yl)-2-{(S)-2-[2-(methoxycarbonylamino)-acetamido]-3-phenylpropanamido}ethyl)phenylsulfamic acid AA49

<5 × 10⁻⁸ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid AA50

0.028 (S)-4-{2-[2-(tert-Butoxycarbonylamino)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamic acid AA51

0.049 [1-(S)-(Phenylthiazol-2-yl)-2-(4- sulfoaminophenyl)ethyl]-carbamic acid tert-butyl ester AA52

0.112 (S)-4-(2-(4-Methylthiazol-2-yl)-2- pivalamidoethyl)phenyl-sulfamicacid AA53

0.085 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-pivalamidoethyl)phenyl- sulfamicacid AA54

0.266 (S)-4-{2-[4-(hydroxymethyl)thiazol-2-yl]-2-pivalamidoethyl}phenyl-sulfamic acid AA55

0.584 (S)-4-{[2-(4-Ethoxycarbonyl)thiazol-2-yl]-2-pivalamidoethyl}phenylsulfamic acid AA56

0.042 (S)-4-(2-(4-Phenylthiazol-2-yl)-2- pivalamidoethyl)phenylsulfamicacid AA57

0.110 4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA58

0.086 4-((S)-2-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenyl-sulfamic acid AA59

0.113 (S)-4-(2-(4-Benzylthiazol-2-yl)-2- pivalamidoethyl)phenylsulfamicacid AA60

0.132 (S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA61

0.138 4-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA62

0.098 (S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA63

0.381 (S)-4-(2-(4-(Biphen-4-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA64

0.033 (S)-4-(2-tert-Butoxycarbonylamino)-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamic acid AA65

0.04 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-propylthiazol-2-yl)ethyl)phenyl sulfamic acid AA66

0.027 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-tert-butylthiazol-2-yl)ethyl)phenyl sulfamic acid AA67

0.18 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)-phenyl sulfamic acid AA68

0.644 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(hydroxymethyl)thiazol-2-yl)ethyl)phenylsulfamic acid AA69

0.167 (S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-ethoxy-2-oxoethyl)thiazol-2-yl)ethyl)phenylsulfamic acid AA70

0.132 (S)-4-(2-(tert-Butoxycarbonyl)-2-(4-(2-(2-methoxy-2- oxoyethylamino)-2-oxoethyl)thiazole-2- yl)ethyl)phenylsulfamic acid AA71

0.555 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(2-pivalamidothiazol-4-yl)ethyl)phenylsulfamic acid AA72

0.308 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(5-phenylthiazol-2-yl)ethyl)-phenyl sulfamic acid AA73

0.253 4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)ethyl)-phenyl sulfamic acid AA74

0.045 4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(thiophen-3-yl)thiazol-2-yl)ethyl)phenyl sulfamic acid AA75

0.05 (S)-{4-[2-(4-Ethylthiazol-2-yl)-2-(phenylacetylamido)ethyl]-phenyl}sulfamic acid AA76

0.012 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid AA77

0.0003 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid AA78

0.028 (S)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA79

0.075 (S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA80

0.056 (S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA81

0.033 (S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA82

0.04 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)phenyl-sulfamic acid AA83

0.014 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic acid AA84

0.008 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic acid AA85

0.002 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfamic acid AA86

0.028 (S)-4-(2-(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamic acid AA87

0.037 (S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamic acid AA88

0.0002 (S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA89

0.003 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic acid AA90

0.01 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic acid AA91

0.006 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic acid AA92

0.002 (S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid AA93

0.002 (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)acetamide]ethyl}phenylsulfamic acid AA94

0.042 (S)-4-[2-(Benzo[d][1,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid AA95

0.003 (S)-4-(2-(5-methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)phenylsulfamic acid AA96

0.046 (S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamic acid AA97

0.0002 4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid AA98

0.0006 4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid AA99

0.002 4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4- yl)ethyl)phenylsulfamic acidAA100

  9 × 10⁻⁶ 4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid

Non-limiting examples of compounds of the invention include:

-   -   (S)-4-[2-Benzamido-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic        acid;    -   (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-fluorophenyl)acetamido]ethyl}phenyl-sulfamic        acid;    -   (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)phenylsulfamic        acid;    -   (S)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic        acid;    -   (S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic        acid;    -   (S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic        acid;    -   (S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic        acid;    -   (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)phenyl-sulfamic        acid;    -   (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic        acid;    -   (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic        acid;    -   (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfamic        acid;    -   (S)-4-(2-(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamic        acid;    -   (S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamic        acid;    -   (S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic        acid;    -   (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic        acid;    -   (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic        acid;    -   (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic        acid;    -   (S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide]ethyl}phenylsulfamic        acid;    -   (S)-4-[2-(Benzo        [d][1,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]-phenylsulfamic        acid;    -   4-((S)-2-(2-(2-Chlorophenyl)acetamido)-2-(2-(thiophene2-yethiazol-4-yl)ethyl)-phenylsulfamic        acid;    -   4-((S)-2-(2-(3-Methoxyphenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4-yl)ethyl)-phenylsulfamic        acid;    -   4-{(S)-2-(3-Phenylpropanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic        acid;    -   4-{(S)-2-(3-(3-Chlorophenyl)propanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid;    -   4-{(S)-2-[2-(3-Fluorophenyl)acetamide]-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid;    -   (S)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamide]-2-(4-ethylthiazol-2-yl]ethyl}-phenylsulfamic        acid;    -   (S)-4-{2-[2-(2,4-Dimethylthiazol-5-yl)acetamide]-2-(4-methylthiazol-2-ylethyl}-phenylsulfamic        acid;    -   (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[3-(thiazol-2-yl)propanamido]ethyl}phenylsulfamic        acid;    -   (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(4-ethylthiazol-2-yl)acetamide]ethyl        }phenyl-sulfamic acid;    -   (S)-4-{2-[2-(3-Methyl-1,2,4-oxadiazol-5-yl)acetamide]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamide]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   (S)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic        acid;    -   (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamido]-ethyl}phenylsulfamic        acid;    -   (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-fluorophenyl)-3-phenylpropanamido]-ethyl}phenylsulfamic        acid;    -   (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamido]-ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   (S)-4-[2-(4-Ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)-ethyl]phenylsulfamic        acid;    -   (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(5-methyl-4-oxohexanamido)ethyl)phenylsulfamic        acid;    -   (S)-4-{2-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   (S)-4-{2-[4-(2,3-Dimethoxyphenyl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamido]ethyl}phenyl-sulfamic        acid;    -   (S)-4-{2-[4-(2,3-Dihydrobenzo [b][1,4]dioxin-6-yl)        -4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   (S)-4-[2-(4-tert-Butoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenyl-sulfamic        acid;    -   (S)-4-[2-(4-Ethoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic        acid;    -   (S)-4-(2-(3-Benz        ylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic acid;    -   4-{[(S)-2-(2-Ethylthiazol-4-yl)-2-(3-(R)-1methoxy-1-oxo-3-phenylpropan-2-yl)ureido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(3-Benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   {4-(S)-[2-Phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl]ethyl}-phenylsulfamic        acid;    -   4-{(S)-2-[(2-Methylthiazol-4-yl)methylsulfonamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   {4-(S)-[2-Phenylmethanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}-sulfamic        acid;    -   {4-(S)-[2-(3-Methoxyphenyl)methanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}sulfamic        acid;    -   (S)-4-{[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylsulfamoyl]methyl}-benzoic        acid methyl ester;    -   (S)-4-[2-(2-Ethylthiazol-4-yl)-2-(1-methyl-1H-imidazol-4-sulfonamido)ethyl]-phenylsulfamic        acid;    -   4-{(S)-2-[2-(Thiophen-2-yl)thiazol-4-yl]-2-(2,2,2-trifluoroethylsulfonamido)-ethyl}phenylsulfamic        acid;    -   {4-(S)-[2-(Phenylethanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]-phenyl}sulfamic        acid;    -   {4-(S)-[3-(Phenylpropanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]-phenyl}sulfamic        acid;    -   (S)-{4-[2-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonylamino)-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamic        acid;    -   4-{(S)-2-(4-Acetamidophenylsulfonamido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(2-cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)-thiazol-2-ylamino]ethyl}phenylsulfamic        acid;    -   (S)-4-(2-(4((2-Methoxy-2-oxoethyl)carbamoyl)thiazole-5-ylamino)2-(2-ethylthiazole-4-yl)ethyl)phenylsulfamic        acid;    -   4-((S)-2-(5-(1-N-(2-Methoxy-2-oxoethyl)-1-H-indol-3-yl)oxazole-2-ylamino)-2-(2-methylthiazol-4-yl)ethyl))phenylsulfamic        acid;    -   4-((S)-2-(5-(2-Methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazol-4-yl)ethyl)-phenylsulfamic        acid;    -   4-((S)-2-(5-((S)-1-(tert-Butoxycarbonyl)-2-phenylethyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylsulfamic        acid;    -   (S)-4-(2-(5-(4-Methoxycarbonyl)phenyl)oxazole-2-ylamino)2-(2-methylthiazole-4-yl)ethyl)phenylsulfamic        acid;    -   (S)-4-(2-(5-(3-Methoxybenzyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)-phenylsulfamic        acid;    -   (S)-4-(2-(2-Methylthiazole-4-yl)2-(5-phenyloxazole-2-ylamino)ethyl)phenyl-sulfamic        acid;    -   4-((S)-2-(2-Cyclopropylthiazol-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2-ylamino)-ethyl)phenylsulfamic        acid;    -   (S)-4-(2-(2-cyclopropylthiazol-4-yl)-2-(4-(4-fluorophenyl)thiazol-2-ylamino)ethyl)-phenylsulfamic        acid;    -   4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2-ylamino)-ethyl)phenylsulfamic        acid;    -   4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2,4-difluorophenyl)thiazol-2-ylamino)-ethyl)phenylsulfamic        acid;    -   (S)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylthiazol-4-yl)ethyl)phenylsulfamic        acid;    -   (S)-{5-[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylamino]-2-methyl-2H-[1,2,4]triazole-3-yl}carbamic        acid methyl ester;    -   4-{(S)-2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[5-(3-Methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[4-(2,4-Difluorophenyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   (S)-4-{2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}-phenylsulfamic        acid;    -   (S)-4-{2-[4-(2-Ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamic        acid;    -   (S)-4-{2-[4-(4-Acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamic        acid;    -   (S)-4-[2-(4-Phenylthiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenylsulfamic        acid;    -   (S)-4-{2-[4-(4-(Methoxycarbonyephenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   (S)-4-[2-(4-(Methoxycarbonyl)thiazol-5-ylamino)-2-(2-phenylthiazole-4-yl)ethyl]-phenylsulfamic        acid;    -   (S)-4-[2-(5-Phenyloxazole-2-ylamino)]-2-(2-phenylthiazole-4-yl)phenylsulfamic        acid;    -   (S)-4-{2-[5-(4-Acetamidophenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)ethyl}phenylsufamic        acid;    -   4-((S)-2-(5-(2,4-Difluorophenyl)oxazole-2-ylamino)-2-(2-phenylthiazole-4-yl)ethyl)phenylsulfamic        acid;    -   4-{(S)-2-[5-(3-Methoxyphenyeoxazol-2-ylamino]-2-[(2-thiophen-2-        yl)thiazole-4-yl]ethyl}phenylsulfamic acid;    -   (S)-4-[2-(4,6-Dimethylpyrimidene-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]-phenylsulfamic        acid;    -   (S)-4-[2-(4-Hydroxy-6-methylpyrimidine-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]phenylsulfamic        acid; 4-{(S)-2-[(S)-2-(te        rt-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(R)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   {1-[1-(5-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methyl        carbamic acid tert-butyl ester;    -   {(S)-2-Phenyl-1-[1-(4-phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethyl-carbamoyl]ethyl}carbamic        acid tert-butyl ester;    -   4-{(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropaneamido-2-(2-phenylthiazole-4-        yl}phenylsulfamic acid;    -   4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(thiazol-2-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-methylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-propylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(4-Cyclopropylthiazol-2-yl)-2-[(S)-2-(methoxycarb        onylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid;    -   4-{(S)-2-(4-Cyclohexylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl        }phenylsulfamic acid;    -   4-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl        }phenylsulfamic acid;    -   4-{(S)-2-Phenyl-1-[1-(2-phenylthiazol-4-yl)-(S)-2-(4-sulfoaminophenyl)ethyl-carbamoyl]ethyl}carbamic        acid tert-butyl ester;    -   4-{(S)-2-(4-Ethyl-5-methylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(2,2,2-trifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido)-2-[4-(3,3,3-trifluoropropyl)thiazol-2-yl]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[4-(2,2-Difluorocyclopropyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(methoxy-methyl)thiazol-2-yl]ethyl}phenylsu        lfamic acid;    -   4-{(S)-2-(4-(Ethoxycarbonylamino)thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(5-phenylthiazol-2-yl))ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[4-(3,4-Dimethylphenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[4-(4-Chlorophenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-phenylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-2-yl)thiazol-2-yl]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbinyl)-3-phenylpropion-amido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(5,6-Dihydro-4H-cyclopentaldlthiazol-2-yl)-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[4-(5-Chlorothiophen-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Ethoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)        ethyl}phenylsulfamic acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-methyl-thiazol-4-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(2-Isopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propan-amido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamido]-2-(2-phenyl-thiazole-4-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(2-methyl-thiazole-4-yl)thiazol-4yl]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-p        yrazine-2-yl)thiazole-4-yl}phenylsulfamic acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(6-methyl-pyridin-3-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]-phenylsulfamic        acid ;    -   4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-        tert-butylthiazol-2-yl)ethyl]-phenylsulfamic acid;    -   4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl)phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   (S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}phenyl-sulfamic        acid;    -   (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonyl)acetamido]ethyl}phenyl-sulfamic        acid;    -   4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-methylbutanamido]-ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-4-methylpentanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid;    -   4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-4-methylpentan-amido]ethyl}phenylsulfamic        acid;    -   4-((S)-2-(4-Ethylthiazol-2-yl)-2-{(S)-2-[2-(methoxycarbonyl)acetamide]-3-phenylpropanamido}ethyl)phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   4-{(S)-2-[(S)-2-(Methoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid; and    -   (S)-4-{2-[2-(tert-Butoxycarbonyl)        acetamide]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamic acid.

Pharmaceutically-Acceptable Salts.

The invention provides the use of pharmaceutically-acceptable salts ofany compound described herein. Pharmaceutically-acceptable saltsinclude, for example, acid-addition salts and base-addition salts. Theacid that is added to the compound to form an acid-addition salt can bean organic acid or an inorganic acid. A base that is added to thecompound to form a base-addition salt can be an organic base or aninorganic base. In some embodiments, a pharmaceutically-acceptable saltis a metal salt. In some embodiments, a pharmaceutically-acceptable saltis an ammonium salt.

Metal salts can arise from the addition of an inorganic base to acompound of the invention. The inorganic base consists of a metal cationpaired with a basic counterion, such as, for example, hydroxide,carbonate, bicarbonate, or phosphate. The metal can be an alkali metal,alkaline earth metal, transition metal, or main group metal. In someembodiments, the metal is lithium, sodium, potassium, cesium, cerium,magnesium, manganese, iron, calcium, strontium, cobalt, titanium,aluminum, copper, cadmium, or zinc.

In some embodiments, a metal salt is a lithium salt, a sodium salt, apotassium salt, a cesium salt, a cerium salt, a magnesium salt, amanganese salt, an iron salt, a calcium salt, a strontium salt, a cobaltsalt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt,or a zinc salt.

Ammonium salts can arise from the addition of ammonia or an organicamine to a compound of the invention. In some embodiments, the organicamine is triethyl amine, diisopropyl amine, ethanol amine, diethanolamine, triethanol amine, morpholine, N-methylmorpholine, piperidine,N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine,pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.

In some embodiments, an ammonium salt is a triethyl amine salt, adiisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, atriethanol amine salt, a morpholine salt, an N-methylmorpholine salt, apiperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt,a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazolesalt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or apipyrazine salt.

Acid addition salts can arise from the addition of an acid to a compoundof the invention. In some embodiments, the acid is organic. In someembodiments, the acid is inorganic. In some embodiments, the acid ishydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbicacid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid,formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid,propionic acid, butyric acid, fumaric acid, succinic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

In some embodiments, the salt is a hydrochloride salt, a hydrobromidesalt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfatesalt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactatesalt, a salicylate salt, a tartrate salt, an ascorbate salt, agentisinate salt, a gluconate salt, a glucaronate salt, a saccaratesalt, a formate salt, a benzoate salt, a glutamate salt, a pantothenatesalt, an acetate salt, a propionate salt, a butyrate salt, a fumaratesalt, a succinate salt, a methanesulfonate salt, an ethanesulfonatesalt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citratesalt, an oxalate salt , or a maleate salt.

Antibodies.

Compounds of the invention can be co-formulated or co-administered withantibodies, for example, anti-VEGF agents. Non-limiting examples of suchantibodies include ranibizumab, bevacizumab, and aflibercept.

An antibody can comprise a heavy chain and a light chain. In someembodiments, the heavy chain comprises SEQ ID NO: 1:GluValGlnLeuValGluSerGlyGlyGlyLeuValGlnProGlyGlyS erLeuArgLeuSerCysAlaAlaSerGlyTyrAspPheThrHisTyrGlyMetAsnTrpValArgGlnAlaProGlyLysGlyLeuGluTrpValGlyTrpIleAsnThrTyrThrGlyGluProThrTyrAlaAlaAspPheLysArgArgPheThrPheSerLeuAspThrSerLysSerThrAl aTyrLeu GlnMetAsnSerLeuArgAlaGluAspThrAlaValTyrTyrCysAlaLysTyrProTyrTyrTyrGlyThrSerHisTrpTyrPheAspValTrpGlyGlnGlyThrLeuValThrValSerSerAlaSerThrLysGlyProSerValPheProLeuAlaProSerSerLysSerThrSerGlyGlyThrAlaAlaLeuGlyCysLeuValLysAspTyrPheProGluProValThrValSerTrpAsnSerGlyAlaLeuThrSerGlyValHisThrPheProAlaValLeuGlnSerSerGlyLeuTyrSerLeuSerSerValValThrValProS erS erSerLeuGlyThrGlnThrTyrIleCysAsnValAsnHisLysProSerAsnThrLysValAspLysLysValGluProLysSerCysAs pLysThrHisLeu.

In some embodiments, the heavy chain is SEQ ID NO: 1.

In some embodiments, the light chain comprises SEQ ID NO: 2:AspIleGlnLeuThrGlnSerProSerSerLeuSerAlaSerValGlyAspArgValThrIleThrCysSerAlaSerGlnAspIleSerAsnTyrLeuAsnTrpTyrGinGlnLysProGlyLysAlaProLysValLeuIleTyrPheThrSerSerLeuHisSerGlyValProSerArgPheSerGlySerGlySerGlyThrAspPheThrLeuThrIleSerSerLeuGlnProGluAspPheAlaThrTyrTyrCysGinGlnTyrSerThrValProTrpThrPheGlyGlnGlyThrLysValGluIleLysArgThrValAlaAlaProSerValPheIlePheProProSerAspGluGlnLeuLysSerGlyThrAlaSerValValCysLeuLeuAsnAsnPheTyrProArgGluAlaLysValGlnTrpLysValAspAsnAlaLeuGlnSerGlyAsnSerGinGluSerValThrGluGlnAspSerLysAspSerThrTyrSerLeuS erSerThr LeuThrGlnSerSerGlyLeuTyrS erLeuSerSerValValThrValProSerSerSerLeuGlyThrGlnThrTyrIleCysAsnValAsnHisLysProSerAsnThrLysValAspLysLysValGluProLysSerCysAspLysThrHisLeu.

In some embodiments, the lgith chain is SEQ ID NO: 2.

An antibody used herein can comprise one or both of SEQ ID NOs: 1 and 2.An antibody used herein can consist of one or both of SEQ ID NOs: 1 and2.

Compositions

Disclosed are compositions and formulations for administration to asubject having one or more conditions, for example, one of the oculardiseases or ocular conditions as described herein. The compositions cancomprise, for example:

a) a compound herein or a pharmaceutically acceptable salt thereof; and

b) a solubilizing system.

The disclosed compositions can comprise from about 0.1 mg/mL to about100 mg/mL of a compound herein.

Solubilizing Systems

The disclosed solubilizing systems can comprise one or morepharmaceutically acceptable agents, which alone or in combinationsolubilize a compound herein or a pharmaceutically acceptable saltthereof.

1. Alcohols

A non-limiting example of a solubilizing agent includes an organicsolvent. Non-limiting examples of organic solvents includes: alcohols,for example, C₁-C₄ linear alkyl, C₃-C₄ branched alkyl, for example,ethanol, glycerin, 2-hydroxypropanol, propylene glycol, maltitol,sorbitol, xylitol and the like; substituted or unsubstituted C₆ or C₁₀aryl; substituted or unsubstituted C₇ or C₁₄ alkylenearyl, for example,benzyl alcohol.

2. Cyclodextrins

A further non-limiting example of a solubilizing agent relates tocyclodextrins: β-cyclodextrin, β-cyclodextrin and β-cyclodextrin andderivatives thereof. Non-limiting examples of cyclodextrin derivativesincludes methyl β-cyclodextrin, β-hydroxypropyl-β-cyclodextrin,sulfobutyl ether-β-cyclodextrin sodium salt, and2-hydroxypropyl-β-cyclodextirn. A cyclodextrin can possess a largecyclic structure with a channel passing through the center of thestructure. The interior of the cyclodextrin can be hydrophobic, andinteract favorably with hydrophobic molecules. The exterior of thecyclodextrin can be highly hydrophilic owing to the several hydroxylgroups exposed to bulk solvent. Capture of a hydrophobic molecule, suchas a compound disclosed herein, in the channel of the cyclodextrin canresult in formation of a complex stabilized by non-covalent hydrophobicinteractions. The complex can be soluble in water, and carry thecaptures hydrophobic molecule into the bulk solvent.

3. Polyvinylpyrrolidione

Another non-limiting example of a solubilizing agent are thepolyvinylpyrrolidones (PVP) having the formula:

wherein the index n is from about 40 to about 200. PVP's can have anaverage molecular weight from about 5500 to about 28,000 g/mol. Onenon-limiting example is PVP-10, having an average molecular weight ofapproximately 10,000 g/mol.

4. Polyakyleneoxides

A further non-limiting example of solubilizing agents includespolyalkyleneoxides, and polymers of alcohols or polyols. Polymers can bemixed, or contain a single monomeric repeat subunit. For example,polyethylene glycols having an average molecular weight of from about200 to about 20,000, for example, PEG 200, PEG 400, PEG 600, PEG 1000,PEG 1450, PEG 1500, PEG 4000, PEG 4600, and PEG 8000. In a furtherembodiment, the compositions comprise one or more polyethylene glycolschosen from PEG 400, PEG 1000, PEG 1450, PEG 4600 and PEG 8000.

Other polyalkyleneoxides are polypropylene glycols having the formula:

HO[CH(CH₃)CH₂O]_(x)H

wherein the index x represents the average number of propyleneoxy unitsin the glycol polymer. As in the case of ethylene glycols, for propyleneglycols the index x can be represented by a whole number or a fraction.For example, a polypropylene glycol having an average molecular weightof 8,000 g/mole (PEG 8000) can be equally represented by the formulae:

HO[CH(CH₃)CH₂O]₁₃₈H or HO[CH(CH₃)CH₂O]_(137.6)H

or the polypropylene glycol can be represented by the common, short handnotation: PEG 8000.

Another example of polypropylene glycols can have an average molecularweight from about 1200 g/mol to about 20,000 g/mol,i.e., a polypropyleneglycol having an average molecular weight of about 8,000 g/mol, forexample, PEG 8000.

Another solubilizing agent is Polysorbate 80 (Tween™ 80) which is anoleate ester of sorbitol and its anhydrides copolymerized withapproximately 20 moles of ethylene oxide for each mole of sorbitol andsorbitol anhydrides. Polysorbate 80 is made up of sorbitanmono-9-octadecanoate poly(oxy-1,2-ethandiyl) derivatives.

Solubilizing agents also include poloxamers having the formula:

HO(CH₂CH₂)_(y1)(CH₂CH₂CH₂O)_(y2)(CH₂CH₂O)_(y3)OH

which are nonionic block copolymers composed of a polypropyleneoxy unitflanked by two polyethyleneoxy units. The indices y¹, y², and y³ havevalues such that the poloxamer has an average molecular weight of fromabout 1000 g/mol to about 20,000 g/mol (PLURONICS™). These compound arecommonly named with the word Poloxamer followed by a number to indicatethe specific co-polymer, for example Poloxamer 407 having two PEG blocksof about 101 units (y¹ and y³ each equal to 101) and a polypropyleneblock of about 56 units and poloxamer 185 [CAS No. 9003-11-6] whereinthe indices y¹, y², and y³ have the average values of 19, 30 and 10respectively. Various poloxamers are available under the trade nameLUTROL™, for example, LUTROL™ F-17. Pluronic F-68 is a commerciallyavailable poloxamer Other non-limiting examples of suitable poloxamersfor use are those such as poloxamer 188, Pluronic F-68, and the like.

5. Polyoxyethylene Glycol Alkyl Ethers

Still further solubilizing agents relate to polyoxyethylene glycol alkylethers having the formula:

RO(CH₂CH₂O)_(n)H

wherein R is a linear or branched alkyl group having from 6 to 20 carbonatoms and n is an integer of about 2 to about 20.

Examples of these compounds are ethoxylate alcohols such as the NEODOL™ethoxylated alcohols. NEODOL™ 23-1 is a mixture of R units that are C₁₂and C₁₃ in length with an average of 1 ethoxy unit. Non-limitingexamples of ethoxylated alcohols include NEODOL™ 23-1, NEODOL™ 23-2,NEODOL™ 23-6.5, NEODOL™ 25-3, NEODOL™ 25-5, NEODOL™ 25-7, NEODOL™ 25-9,PLURONIC™ 12R3, and PLURONIC™ 25R2.

6. Polyoxypropylene Glycol Alkyl Ethers

Yet another example of a solubilizing agent includes polyoxypropyleneglycol alkyl ethers having the formula:

RO(CH₂CH(CH₃)O)_(n)H

wherein R is a linear or branched alkyl group having from 6 to 20 carbonatoms and n is an integer of about 2 to about 20.

The formulator, however, can use any solubilizing agent or agents incombination to affect the solubility of a compound herein.

One aspect of the disclosure relates to compositions and formulationscomprising the herein disclosed compounds or a pharmaceuticallyacceptable salt thereof. Compositions containing the disclosedinhibitors can comprise:

a) a compound herein or a pharmaceutically acceptable salt thereof; and

b) a solubilizing system.

Another aspect of the disclosed compositions relates to Tie-2 activatorsor HPTP-β inhibitors or a pharmaceutically acceptable salt thereofhaving the formula:

wherein R² and R⁴ are chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched,        or C₃-C₆ cyclic alkyl;    -   iii) substituted or unsubstituted phenyl; or    -   iv) substituted or unsubstituted thiophenyl;    -   R¹ is C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl;    -   R^(5a) is chosen from:    -   i) hydrogen;    -   ii) C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; or    -   iii) benzyl; or    -   a pharmaceutically acceptable salt thereof.

A non-limiting embodiment of this aspect relates to HPTP-β inhibitorshaving the formula:

wherein R² and R⁴ are chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched,        or C₃-C₆ cyclic alkyl;    -   iii) substituted or unsubstituted phenyl; or iv) substituted or        unsubstituted thiophenyl;    -   R¹ is C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; or    -   a pharmaceutically acceptable salt.

An aspect of the disclosed compositions relates to HPTP-β inhibitors ora pharmaceutically acceptable salt thereof having the formula:

wherein R² is chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched,        or C₃-C₆ cyclic alkyl;    -   iii) substituted or unsubstituted thiophenyl;    -   R¹ is C₁-C₃ alkyl substituted by one or more optionally        substituted phenyl; or    -   a pharmaceutically acceptable salt thereof.

In one iteration the substitutions for phenyl are chosen from fluoro,chloro and methoxy.

An aspect of the disclosed compositions relates to HPTP-β inhibitors ora pharmaceutically acceptable salt thereof having the formula:

wherein R is chosen from, for example, benzyl, phenylethyl,(2-methylthiazol-4-yl)methyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, (5-(4-chlorobenzamide)methyl)thiopen-2-yl, and(5-(methoxycarbonyemethyl)-1,3,4-thiadiazol-2-yl.

Formulation Example 1

In one non-limiting example, compositions of compounds herein areprepared as follows. For example, about 100 mg of a sterile powder of,for example,4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid is diluted in, for example, about 100 mL water to form a firstcomposition. To the composition can be added, for example, 250 mg ofhydroxypropyl beta cyclodextrin (HP(βCD). Depending upon theformulation, the administrator of the compound can withdraw a sufficientamount such that the subject is injected subcutaneously with an amountthat provides from about 5 mg to about 50 mg of the compound. Theformulator, however, can prepare a composition having any concentrationconvenient or desirable. Non-limiting examples according to thisembodiment include the following.

TABLE XXII Compound (mg) HPβCD (mg) Water (mL) 50 250 25 50 250 50 50250 75 50 250 100 100 250 25 100 250 50 100 250 75 100 250 100 50 250200 50 250 300 50 250 400 50 250 500 100 250 200 100 250 300 100 250 400100 250 500

Formulation Example 2

This formulation example relates to compositions comprising4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid, having the formula:

and pharmaceutically acceptable salts thereof.

Formulation Example 2 comprises:

-   -   a)        4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) a solubilizing system; and    -   c) a carrier system.

The compositions of Formulation Example 2 are formulated to deliver anamount of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid in the free acid form. For example, a composition which comprises10 mg/mL of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid can have either 10 mg/mL of the free acid or an amount of apharmaceutically acceptable salt in an amount sufficient to deliver 10mg/mL of the free acid. As an example, a composition formulated todeliver 10 mg/mL of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamicacid can comprise either 10 mg/mL of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or alternatively 10.4 mg/mL of the sodium salt, (sodium(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamate).Therefore, a composition which delivers from about 0.1 mg/mL to about 60mg/mL of(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamicacid can comprise an amount of pharmaceutically acceptable salt thereofto deliver from about 0.1 mg/mL to about 60 mg/mL of the compound.

Therefore, when a composition according to Formulation I comprises anamount of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid per mL, it is understood that this amount is the amount of freeacid that is delivered and if a salt form of the compound is used in thecomposition, the amount of the salt form can therefore reflect thedifference in molecular weight between the free acid and the salt form.The following example demonstrates this equivalency.

A composition delivering 10 mg/mL of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid, comprises:

-   -   a) 10 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-        yl)thiazol-4-yl]ethyl}phenylsulfamic acid; or about 10.4 mg/mL        of sodium        (4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamate;        or about 10.3 mg/mL of ammonium        (4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamate,        and the like;    -   b) an amount of a solubilizing system; and    -   c) a carrier system.

The disclosed compositions according to Formulation Example 2 accordingto Formulation Example 2 comprise from about 0.1 mg/mL to about 60 mg/mLof4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof.

In one aspect the disclosed compositions according to FormulationExample 2 comprise from about 0.5 mg/mL to about 60 mg/mL of a compoundherein or a pharmaceutically acceptable salt thereof. In one embodiment,the composition comprises from about 5 mg/mL to about 40 mg/mL of acompound herein or a pharmaceutically acceptable salt thereof. Inanother embodiment, the composition comprises from about 10 mg/mL toabout 40 mg/mL of a compound herein or a pharmaceutically acceptablesalt thereof. In a further embodiment, the composition comprises fromabout 10 mg/mL to about 30 mg/mL of a compound herein or apharmaceutically acceptable salt thereof. In a still further embodiment,the composition comprises from about 0.5 mg/mL to about 20 mg/mL of acompound herein or a pharmaceutically acceptable salt thereof. In afurther embodiment the composition comprises from about 1 mg/mL to about20 mg/mL weight by volume of a compound herein or a pharmaceuticallyacceptable salt thereof. In a further embodiment, the compositioncomprises from about 15 mg/mL to about 30 mg/mL weight by volume of acompound herein or a pharmaceutically acceptable salt thereof. Inanother embodiment, the composition comprises from about 10 mg/mL toabout 50 mg/mL weight by volume of a compound herein or apharmaceutically acceptable salt thereof.

Particular embodiments of the disclosed compositions according toFormulation Example 2, can comprise, for example, 1 mg/mL, 2 mg/mL, 3mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL,11 mg/mL 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 23 mg/mL, 24 mg/mL, 25mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29 mg/mL, 30 mg/mL, 31 mg/mL 32mg/mL, 33 mg/mL, 34 mg/mL, 35 mg/mL, 36 mg/mL, 37 mg/mL, 38 mg/mL, 39mg/mL, 40 mg/mL, 41 mg/mL 42 mg/mL, 43 mg/mL, 44 mg/mL, 45 mg/mL, 46mg/mL, 47 mg/mL, 48 mg/mL, 49 mg/mL, 50 mg/mL, 51 mg/mL 52 mg/mL, 53mg/mL, 54 mg/mL, 55 mg/mL, 56 mg/mL, 57 mg/mL, 58 mg/mL, 59 mg/mL, and60 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL,about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9mg/mL, about 10 mg/mL, about 11 mg/mL about 12 mg/mL, about 13 mg/mL,about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL about 22 mg/mL,about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27mg/mL, about 28 mg/mL, about 29 mg/mL, about 30 mg/mL, about 31 mg/mLabout 32 mg/mL, about 33 mg/mL, about 34 mg/mL, about 35 mg/mL, about 36mg/mL, about 37 mg/mL, about 38 mg/mL, about 39 mg/mL, about 40 mg/mL,about 41 mg/mL about 42 mg/mL, about 43 mg/mL, about 44 mg/mL, about 45mg/mL, about 46 mg/mL, about 47 mg/mL, about 48 mg/mL, about 49 mg/mL,about 50 mg/mL, about 51 mg/mL about 52 mg/mL, about 53 mg/mL, about 54mg/mL, about 55 mg/mL, about 56 mg/mL, about 57 mg/mL, about 58 mg/mL,about 59 mg/mL, and about 60 mg/mL of the compound herein.

A formulation that is disclosed herein can be made more soluble by theaddition of an additive or agent. The improvement of solubility of theformulation can increase by about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about55%, about 60%, about 65%, about 70%, about 75% about 80%, about 85%,about 90%, about 95%, about 100%, about 110%, about 120%, about 130%,about 140%, about 150%, about 160%, about 170%, about 180%, about 190%,about 200%, about 225%, about 250%, about 275%, about 300%, about 325%,about 350%, about 375%, about 400%, about 450%, or about 500%.

A formulation disclosed herein can be stable for about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 4weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks,about 3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, or about one year. A formulation disclosed herein can be stable,for example, at about 0° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., about 35° C., about 40° C.,about 45° C., about 50° C., about 60° C., about 70° C., or about 80° C.

Solubilizing Systems.

The disclosed compositions according to Formulation Example 2 cancomprise, for example, from a ratio of about 1 part of a compound hereinor a pharmaceutically acceptable salt thereof to 4 parts solubilizingsystem (1:4) to about 1 part of the compound or a pharmaceuticallyacceptable salt thereof to about 8 parts solubilizing system (1:8).

The disclosed solubilizing systems comprise2-hydroxypropyl-beta-cyclodextrin (HPβ-CD).2-Hydroxypropyl-β-cyclodextrin [CAS No. 128446-35-5] is commerciallyavailable as Cavitron™. 2-Hydroxypropyl-β-cyclodextrin, also describedherein as hydroxypropyl-β-cyclodextrin,2-hydroxypropyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin orHPβCD, can be represented by either of the following formulae:

The average molecular weight of HPβCD as provided under the nameCavitronβ, is approximately 1396 Da wherein the average degree ofsubstitution is from about 0.5 to about 1.3 units of 2-hydroxypropyl perring glucose unit. For calculation purposes it is convenient for theformulator to use 1400 Da as the molecular weight of HPβCD.

For example, a composition according to Formulation Example 2 comprisingfrom about 0.1 mg/mL to about 60 mg/mL of the compound or apharmaceutically acceptable salt thereof can comprise from about 0.25mg/mL to about 500 mg/mL of HPβCD. Stated another way, a compositioncomprising about 10 mg/mL of a disclosed composition can comprise from40 mg/mL (1:4) to about 80 mg/mL (1:8) of HPβCD. The formulator canadjust the ratios of compound to HPβCD based upon compositionparameters, for example, choice and amount of a tonicity agent, pH, andthe like.

The following are non-limiting examples of ratios of compound or apharmaceutically acceptable salt and HPβCD: 1:4, 1:4.1, 1:4.2, 1:4.3,1:4.4; 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5, 1:5.1, 1:5.2, 1:5.3,1:5.4; 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9,1:6, 1:6.1, 1:6.2, 1:6.3,1:6.4; 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, 1:7, 1:7.1, 1:7.2, 1:7.3,1:7.4; 1:7.5, 1:7.6, 1:7.7, 1:7.8, 1:7.9, and 1:8, or alternatively,about 1:4, about 1:4.about 1, about 1:4.2, about 1:4.3, about 1:4.4;about 1:4.5, about 1:4.6, about 1:4.7, about 1:4.8, about 1:4.9, about1:5, about 1:5.about 1, about 1:5.2, about 1:5.3, about 1:5.4; about1:5.5, about 1:5.6, about 1:5.7, about 1:5.8, about 1:5.9, about 1:6,about 1:6.1, about 1:6.2, about 1:6.3, about 1:6.4; about 1:6.5, about1:6.6, about 1:6.7, about 1:6.8, about 1:6.9, about 1:7, about 1:7.1,about 1:7.2, about 1:7.3, about 1:7.4; about 1:7.5, about 1:7.6, about1:7.7, about 1:7.8, about 1:7.9, and about 1:8.

As such, the compositions can comprise an amount of HPβCD suitable forachieving the desired properties of the composition, i. e. ,concentration of a compound, such as4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid , the desired viscosity, and the desired osmolarity. The amount ofHPβCD can vary depending upon the amount of the compound that theformulator desires to deliver in a single dose.

Carrier System

The disclosed compositions according to Formulation Example 2 comprisefrom about 1.35% to about 90% weight by volume of a carrier system. Theamount of carrier system present is based upon several different factorsor choices made by the formulator, for example, the final concentrationof the compound and the amount of solubilizing agent.

The following is a non-limiting example of a composition comprising 15mg/mL of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid:

a) 15 mg of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid;

b) 93.75 mg of 2-hydroxypropyl-beta-cyclodextrin; and

c) the balance a carrier system to a volume of 1 mL.

In one aspect, the carrier system comprises:

i) one or more tonicity agents; and

ii) water.

Non-limiting examples of tonicity agents include dextrose, mannitol andglycerin.

The formulator can utilize more than one tonicity agent when formulatingthe disclosed compositions according to Formulation Example 2. Thetonicity agent can comprise from about 0.5% to about 5% weight by volumeof the final composition. In non-limiting examples, when preparing thefinal composition, the tonicity agent may be combined with4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid before mixing with the carrier system. Alternately, whenreconstituting the final composition the formulator can use commerciallyavailable solutions containing a tonicity agent, for example, 5%Dextrose Injection, USP.

The osmolarity of the disclosed compositions according to FormulationExample 2 can be within any range chosen by the formulator. In oneaspect the osmolarity is from about 250 to about 350 mOsm/L. In oneembodiment of this aspect of the disclosed osmolarity is from about 270to about 310 mOsm/L.

The pH of the disclosed compositions according to Formulation Example 2can be from about 6 to about 8. If the pH is outside the range desiredby the formulator, the pH can be adjusted by using sufficientpharmaceutically-acceptable acids and bases.

One aspect of the disclosed compositions according to FormulationExample 2 relates to compositions comprising4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or pharmaceutically acceptable salts thereof.

One embodiment of this aspect of the disclosed compositions according toFormulation Example 2 comprises:

-   -   a) from about 9.5 mg/mL to about 10.5 mg/mL of the        4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 59 mg/mL to about 65.5 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 2 comprises:

-   -   a) about 10 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 62.5 mg/mL of 2-hydroxypropyl-(3-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 10 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 62.5 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.    -   c) a carrier system containing        -   i) dextrose; and        -   ii) water        -   wherein the dextrose is present in an amount such that the            concentration of dextrose in the final composition is 2%.

Another embodiment of this aspect of the disclosed compositionsaccording to Formulation Example 2 comprises:

-   -   a) from about 14 mg/mL to about 16 mg/mL of the        4-{(8)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 87.5 mg/mL to about 100 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 2 comprises:

-   -   a) about 15 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 93.75 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 15 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 93.75 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

A further embodiment of this aspect of the disclosed compositionsaccording to Formulation Example 2 comprises:

-   -   a) from about 18.5 mg/mL to about 21.5 mg/mL of the        4-{(8)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 115.6 mg/mL to about 134.5 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 2 comprises:

-   -   a) about 20 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 125 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 20 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 125 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

A further embodiment of this aspect of the disclosed compositionsaccording to Formulation Example 2 comprises:

-   -   a) from about 24 mg/mL to about 26 mg/mL of the        4-{(8)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 150 mg/mL to about 162.5 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 2 comprises:

-   -   a) about 25 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 156.25 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 25 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 156.25 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

A further embodiment of this aspect of the disclosed compositionsaccording to Formulation Example 2 comprises:

-   -   a) from about 27.5 mg/mL to about 32 mg/mL of the        4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 170 mg/mL to about 200 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 2 comprises:

-   -   a) about 30 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 187.5 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 30 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 187.5 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

Another embodiment of this aspect of the disclosed compositionsaccording to

Formulation Example 2 comprises:

-   -   a) from about 34 mg/mL to about 36 mg/mL of the        4-{(8)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 212.5 mg/mL to about 223.5 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   ) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 2 comprises:

-   -   a) about 35 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 218.75 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 35 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 218.75 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

Another embodiment of this aspect of the disclosed compositionsaccording to Formulation Example 2 comprises:

-   -   a) from about 38 mg/mL to about 42 mg/mL of the        4-{(8)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 237.5 mg/mL to about 262.5 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 2 comprises:

-   -   a) about 40 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 250 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 40 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 250 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

EXAMPLE 25

To a 100 mL volumetric flask containing water (85 mL) was charged HPβCD(10 g) and dextrose (1.5 g). The solution was stirred for 1 hour at 20°C. then the volume made up to 100 mL with additional distilled water.The resulting solution comprised 10% HPβCD and 1.5% dextrose.

In a like manner, solutions comprising 15% HPβCD/1.5% dextrose and 17.5%HPβCD/1.5% dextrose were prepared. These stock solutions were used forthe following experiments.

In a 25 mL volumetric flask is added the stock solution comprising 10%HPβCD/1.5% dextrose followed by the addition of sodium4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamate(550 mg). The total volume was made up to 25 mL by the addition ofdistilled water. The resulting solution had a nominal concentration of4-{(8)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamicacid of 20 mg/mL after applying a molecular weight correction factor.

Similarly, to a stock solution comprising 10% HPβCD/1.5% dextrose wasadded4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamate(687 mg). After dilution to 25 mL the resulting solution had a nominalconcentration of4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamicacid of 25 mg/mL after applying a molecular weight correction factor.

Compositions comprising 15% HPβCD/1.5% dextrose and 687 mg and 825 mg of4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamatewere also prepared. Likewise, compositions comprising 17.5% HPβCD/1.5%dextrose and 825 mg and 962.5 mg of Compound A-Na were also prepared.

The following Table XXIII describes the test compositions each totaling25 mL wherein4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamateis listed as Compound A-Na.

TABLE XXIII Stock 10% HPβCD/ 15% HPβCD/ 17.5% HPβCD/ Solution 1.5% dex.1.5% dex. 1.5% dex. Comp 550 687 687 825 825 962.5 A-Na (mg) Comp A 2025 25 30 30 35 mg/mL

To 3 one-dram vials was transferred approximately 3 mL of each of the 6solutions above. One vial of each was held at 4° C., 20° C. and 40° C.The vials were evaluated weekly for one month then monthly for threemonths.

After 3 months none of the vials appeared hazy or had any precipitate orflocculent.

The above compositions where then further processed and submitted for invivo testing.

Preparation of Compositions for Subcutaneous Deliver Via 0.75 mL Singleuse Syringes EXAMPLE 26

To 200 mL of Mille-Q water was added 2-hydroxypropyl-β-cyclodextrin (50g) (Ashland/ISP Cavitron W7HP7) with stirring. Next, dextrose (96%) (1.3g) (Sigma Aldrich) was added and the solution was stirred until all thesolids were dissolved. Sodium(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(2-thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate(10.82 g) was added and the solution was stirred until the solids weredissolved. The resulting solution had a pH value of 7.26 and a densityof 1.07 g/mL. Final solution filtered through Millipore™ MilliPak20-0.22 micron PVDF filter. A calibrated peristaltic pump was used todispense 0.75 mL of the final solution into HYpak 0.75 mL syringeshaving 27 g staked needles and Hypak FluroTec stoppers.

EXAMPLE 27

To 200 mL of Milli-Q water was added 2-hydroxypropyl-β-cyclodextrin(43.75 g) (Ashland/ISP Cavitron W7HP7) with stirring. Next, Dextrose(96%) (2.61 g) (Sigma Aldrich) was added and the solution was stirreduntil all the solids were dissolved. Sodium(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(2-thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate(10.85 g) was added and the solution was stirred until the solids weredissolved. The resulting solution had a pH value of 7.32 which wasadjusted to 7.04 with 1N HC1(0.5mL). The final solution had a density of1.064 g/mL. Final solution filtered through Millipore™ MilliPak 20-0.22micron PVDF filter. A calibrated peristaltic pump was used to dispense0.75 mL of the final solution into HYpak 0.75 mL syringes having 27 gstaked needles and Hypak FluroTec stoppers.

EXAMPLE 28

To 200 mL of Milli-Q water was added 2-hydroxypropyl-β-cyclodextrin(56.25 g) (Ashland/ISP Cavitron W7HP7) with stirring. Next, Dextrose(96%) (1.3 g) (Sigma

Aldrich) was added and the solution was stirred until all the solidswere dissolved. Sodium(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(2-thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate(10.86 g) was added and the solution was stirred until the solids weredissolved. The resulting solution had a pH value of 7.24 and a densityof 1.074 g/mL. Final solution filtered through Millipore™ MilliPak20-0.22 micron PVDF filter. A calibrated peristaltic pump was used todispense 0.75 mL of the final solution into HYpak 0.75 mL syringeshaving 27 g staked needles and Hypak FluroTec stoppers.

In the above examples, the formulator can alternatively heat thesolution to about 40° C. to aid in solubilizing the components. Inaddition, the formulator can filter the solutions at any point in theprocess to remove any undissolved material.

The following is a non-limiting example of the process for preparing apharmaceutical composition suitable for subcutaneous delivery of thedisclosed compositions according to Formulation Example 2 comprising4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamicacid or a pharmaceutically acceptable salt to humans

Step-wise Manufacturing Process: 20 mg of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid per mL solution

-   -   1. Add approximately 16.0 kg of United States Pharmacopeia (USP)        Sterile Water for

Injection to an appropriately-sized glass vessel..

-   -   2. Add 2812.5 g of 2-hydroxylpropyl-beta-cyclodextrin (HP(3CD)        (USP) to the glass flask and mix for a minimum of 5 minutes or        until dissolved.    -   3. Add 450 g of        4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic        acid (as the sodium salt factored for purity, volatiles and        water) to the glass flask and mix for a minimum of 30 minutes or        until all of the solids are dissolved.    -   4. Add 450 g of D-glucose (Dextrose) Anhydrous (USP) to the        glass flask and mix for a minimum of 5 minutes or until all of        the solids are dissolved.    -   5. Transfer the solution to a 36 L glass formulation vessel        using a peristaltic pump.    -   6. QS the formulation to 22.7 kg by adding Sterile Water for        Injection, USP and mix for a minimum of 30 minutes or until        dissolved.    -   7. Adjust the pH to obtain a pH of 6.6-7.0.    -   8. Add sufficient quantities of Sterile Water for Injection, USP        to the batch to obtain the final batch weight of 23.7 kg (22.5        L * 1.052 g/mL -specific gravity) and mix for a minimum of 10        minutes or until all of the solids are dissolved.    -   9. Filter through two filters (Sartopore 2 XLG Midicap filters)        connected in series into a similar 36 L glass fill vessel.    -   10. Fill into various syringes: i.e., 0.75 mL syringe (to        deliver 15 mg of        4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic        acid), 1 mL syringe (20 mg of        4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic        acid), etc.

Dry Compositions

The disclosed compositions according to Formulation Example 2 can bere-constituted from a dry or solid composition. As such the dry or solidcompositions comprise:

-   -   a)        4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic        acid or a pharmaceutically acceptable salt thereof; and    -   b) HPβCD.

The dry compositions are prepared such that upon re-constitution with acarrier system described herein, the resulting aqueous compositiondelivers from about 0.5 mg/mL to about 60 mg/mL of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof.

As in the aqueous compositions described herein, the ratio of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid to HPβCD is from about 1:4 to about 1:8. The amount of dry materialin a container that can be reconstituted can vary depending upon thenumber of doses of dry material desired. For example, a single 15 mg/mLdose of the compound can be sealed or otherwise placed in a containerthat has an exact volume such that when the composition isre-constituted, an amount of composition that is reconstituted has 15mg/mL of a compound.

In another embodiment, the dry compositions comprise:

-   -   a)        4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) HPβCD; and    -   c) a tonicity agent;        wherein the ratio of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid to HPβCD is from about 1:4 to about 1:8 and the tonicity        agent is present in an amount such that the re-constituted        formula comprises from about 0.5% to about 5% weight to volume        of the tonicity agent.

The use of further solubilizing agents was examined In a first test offurther solubilizing agents, polyvinylpyrrolidone (PVP) having theformula:

wherein the index n is from about 40 to about 200 was tested. PVP's havean average molecular weight from about 5500 to about 28,000 g/mol. Onenon limiting example is PVP-10 having an average molecular weight ofapproximately 10,000 g/mol available from Sigma-Aldrich.

The follow experiments were undertaken to determine the suitability offormulating a composition comprising PVP and HPβCD as a solubilizingsystem for sodium4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamate.The following is a non-limiting example.

EXAMPLE 29

To a 25 mL volumetric flask containing 20 mL of distilled water ischarged hydroxylpropyl-β-cyclodextrin (2.5 g) and polyvinylpyrrolidone,PVP-10, (0.125 g) and the solution stirred at room temperature for 0.5hours. Additional water was added to bring the final volume to 25 mL.The following compositions were prepared according to this procedure.

TABLE XXIV Experiment No. Concentration HPβCD (g) PVP-10 (g) 1 10%HPβCD + 0.5% PVP 2.5 0.125 2 10% HPβCD + 1.0% PVP 2.5 0.25 3 10% HPβCD +2.0% PVP 2.5 0.5 4 15% HPβCD + 0.5% PVP 3.75 0.125 5 15% HPβCD + 1.0%PVP 3.75 0.25 6 15% HPβCD + 2.0% PVP 3.75 0.5

To each solution was added sodium(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(thiophen-2-yl)thiazol-4- yl)ethyl}-phenyl)sulfamate (1300 mg) was added tosolutions 1, 2 and 3 and stirred for 6 hours at room temperature toprovide a nominal concentration of 52 mg/mL. Similarly, the compound(1500 mg) was added to solutions 4 5, and 6 and stirred for 6 hours atroom temperature to provide a nominal concentration of 60 mg/mL.Table)0(V lists the solution obtained herein below.

TABLE XXV Experiment Comp. A-Na HPβCD PVP-10 No. mg/mL mg/mL mg/mL 7 52100 5 8 52 100 10 9 52 100 20 10 60 150 5 11 60 150 10 12 60 150 20

Summary of Results

All compositions comprising polyvinylpyrrolidones were hazy upon 2 hoursof standing or yielded a suspension. Experiments 10, 11 and 12 yielded agel upon standing. Compositions formulated in the manner of Example 30having only a PVP (no HP(3CD) formed a hazy initial solution that setupas a gel and remained such upon standing for 3 days.

In one aspect of the disclosed compositions according to FormulationExample 2, the compositions do not comprise poylvinylpyrrolidone or aderivative thereof. Compositions which gel upon standing cannot beinjected parentally, e.g., subcutaneously and, therefore, areincompatible with the disclosed compositions according to FormulationExample 2. This is because the temperature during shipment and storageof the compositions result in physical properties, i.e., formation of agel that cannot be administered by the artisan.

In a further aspect of the disclosed compositions according toFormulation Example 26, the compositions do not comprisepoylvinylpyrrolidone or a derivative thereof in combination with2-hydroxypropyl-β-cyclodextrin.

The follow experiments were undertaken to determine the suitability offormulating a composition comprising a quaternary ammonium salt, PVP andHPβCD as a solubilizing system for sodium4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamate.The following is a non-limiting example

Preparation of Stock Solution

Benzalkonium chloride (BAC; alkylbenzyldimethylammonium chloride, alkyl:C₈-C₁₈ available from Sigma-Aldrich) (36.3 mg) was added to water (200mL) in a 250 mL volumetric flask. The mixture was stirred for 10 hoursin a 35° C. water bath until the solution was clear.2-Hydroxy-propyl-β-cyclodextrin (27.5 g) was added and the volume madeup to 250 mL with the addition of more water.

EXAMPLE 30

To a 25 mL volumetric flask is added the stock solution (22.8 mLfollowed by polyvinylpyrrolidone (Povidone 437190™ ex Sigma-Aldrich)(0.25 g) and sodium(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate(1.14 g). The volume was made up to 25 mL with the addition of morestock solution. The resulting suspension was stirred for 1 hour at 20°C. The solution was filtered through 0.65 micron then 0.45 micron filterpaper and 5 mL of the filtrate was transferred to 3 separate vials. Onevial was held at each of the following temperatures 4° C., 20° C. and40° C.

EXAMPLE 31

To a 25 mL volumetric flask is added the stock solution (22.8 mLfollowed by polyvinylpyrrolidone (Povidone 437190™ ex Sigma-Aldrich)(0.375 g) and sodium(4-{(S)-2-[(S)-2-methoxycarbonaylamino)-3-phenylpropanamido]-2-(2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate(1.14 g). The volume was made up to 25 mL with the addition of morestock solution. The resulting suspension was stirred for 1 hour at 20°C. The solution was filtered through 0.65 micron then 0.45 micron filterpaper, however, the flow rate was extremely slow. 5 mL of the filtratewas transferred to 3 separate vials. One vial was held at each of thefollowing temperatures 4° C., 20° C. and 40° C.

EXAMPLE 32

To a 25 mL volumetric flask is added the stock solution (22.8 mLfollowed by polyvinylpyrrolidone (Povidone 437190™ ex Sigma-Aldrich)(0.5 g) and sodium(4-{(S)-2-[S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate(1.43 g). The volume was made up to 25 mL with the addition of morestock solution. The resulting suspension was stirred for 1 hour at 20°C. Attempt to filter solution through 0.65 micron then 0.45 micronfilter paper and 5 mL of the filtrate was unsuccessful. Example 9 wasabandoned.

Table XXVI below outlines the compositions of Examples 7-9: sodium4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamateis referred to as Compd A-Na in the table.

TABLE XXVI Ex. 11 Ex. 12 Ex. 13 Components (mg/mL) (mg/mL) (mg/mL) CompdA-Na 40 40 50 PVP 10 15 20 BAC 0.13 0.13 0.13 HPβCD 100 100 100

Summary of Results

Example 7: 4° C. sample gelled and remained so for 8 days.

-   -   20° C. a suspension was observed.    -   40° C. solution remained clear for 8 days.

Example 8: 4° C. sample gelled and remained so for 8 days.

-   -   20° C. the solution appeared hazy.    -   40° C. solution remained clear for 8 days.

In some embodiments of the disclosed compositions according toFormulation Example 2, the compositions do not comprise benzalkoniumchloride or other quaternary ammonium salt. In some embodiments of thedisclosed compositions according to Formulation Example 2, thecompositions do comprise benzalkonium chloride or other quaternaryammonium salt.

In a further aspect of the disclosed compositions according toFormulation Example 2, in some embodiments, the compositions do comprisebenzalkonium chloride or other quaternary ammonium salt in combinationwith 2-hydroxy-propyl-β-cyclodextrin, and in some embodiments, thecompositions do not comprise benzalkonium chloride or other quaternaryammonium salt in combination with 2-hydroxy-propyl-β-cyclodextrin.

In a still further aspect of the disclosed compositions according toFormulation Example 2, in some embodiments, the compositions do comprisebenzalkonium chloride or other quaternary ammonium salt in combinationwith polyvinylpyrrolidone or a derivative thereof, and in someembodiments, the compositions do not comprise benzalkonium chloride orother quaternary ammonium salt in combination with polyvinylpyrrolidoneor a derivative thereof.

In a yet further aspect of the disclosed compositions according toFormulation Example 2, in the somebodiments, the compositions docomprise benzalkonium chloride or other quaternary ammonium salt incombination with polyvinylpyrrolidone or a derivative thereof and2-hydroxypropyl-β-cyclodextrin, and in some embodiments, thecompositions do not comprise benzalkonium chloride or other quaternaryammonium salt in combination with polyvinylpyrrolidone or a derivativethereof and 2-hydroxypropyl-β-cyclodextrin.

Some embodiments do, and some embodiments do not contain polyethyleneglycol. Non-limiting examples of polyethylene glycols include thosehaving an average molecular weight of from about 200 to about 20,000,for example, PEG 200, PEG 400, PEG 600, PEG 1000, PEG 1450, PEG 1500,PEG 4000, PEG 4600, and PEG 8000. In a further embodiment, thecompositions comprise one or more polyethylene glycols chosen from PEG400, PEG 1000, PEG 1450, PEG 4600 and PEG 8000. Non-limiting examplesinclude any disclosed herein.

The disclosed compositions according to Formulation Example 2 optionallycomprise from about 0.001% to about 0.5%, or from about 0.001% to about1% weight by volume pharmaceutically acceptable preservatives. Onenon-limiting example of a suitable preservative is benzyl alcohol.

In some embodiments, the compositions according to Formula Example 1consists essentially of4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof, a solubilizingsystem and a carrier system.

In some embodiments, the compositions according to Formula Example 1consists of4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof, a solubilizingsystem and a carrier system.

In some embodiments, the compositions according to Formula Example 1consists essentially of4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof, a solubilizingsystem and a carrier system, wherein the solubilizing system consists ofHPβCD.

In still other embodiments, the compositions according to FormulaExample 1 consists essentially of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamicacid or a pharmaceutically acceptable salt thereof, a solubilizingsystem and a carrier system wherein the carrier system consists of waterand a tonicity agent.

In yet other embodiments, the compositions according to Formula Example1 consists essentially of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamicacid or a pharmaceutically acceptable salt thereof, a solubilizingsystem and a carrier system, wherein the solubilizing system consists ofHPβCD and wherein the carrier system consists of water and a tonicityagent.

In still other embodiments, the compositions according to FormulaExample 1 consists essentially of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamicacid or a pharmaceutically acceptable salt thereof, HPβCD, a tonicityagent, water and optionally a preservative.

In a particular embodiment the compositions according to Formula Example1 consists of4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof, HPβCD, a tonicityagent, water and optionally a preservative.

The disclosed compositions according to Formulation Example 2 canfurther comprise from about 0.01% to about 1% weight by volumepharmaceutically acceptable preservatives. One non-limiting example of asuitable preservative is benzyl alcohol, for example, 0.9% benzylalcohol.

Excipients.

A pharmaceutical composition of the invention can be a combination ofany pharmaceutical compounds described herein with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Pharmaceutical compositions can be administered intherapeutically-effective amounts as pharmaceutical compositions byvarious forms and routes including, for example, intravenous,subcutaneous, intramuscular, oral, rectal, aerosol, parenteral,ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topicaladministration.

A pharmaceutical composition can be administered in a local or systemicmanner, for example, via injection of the compound directly into anorgan, optionally in a depot or sustained release formulation.Pharmaceutical compositions can be provided in the form of a rapidrelease formulation, in the form of an extended release formulation, orin the form of an intermediate release formulation. A rapid release formcan provide an immediate release. An extended release formulation canprovide a controlled release or a sustained delayed release.

For oral administration, pharmaceutical compositions can be formulatedreadily by combining the active compounds withpharmaceutically-acceptable carriers or excipients. Such carriers can beused to formulate tablets, powders, pills, dragees, capsules, liquids,gels, syrups, elixirs, slurries, suspensions and the like, for oralingestion by a subject.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Cores can be provided with suitablecoatings. For this purpose, concentrated sugar solutions can be used,which can contain an excipient such as gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments can be added to the tablets or drageecoatings, for example, for identification or to characterize differentcombinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. In someembodiments, the capsule comprises a hard gelatin capsule comprising oneor more of pharmaceutical, bovine, and plant gelatins. A gelatin can bealkaline-processed. The push-fit capsules can contain the activeingredients in admixture with filler such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,stabilizers. In soft capsules, the active compounds can be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. Stabilizers can be added. All formulationsfor oral administration are provided in dosages suitable for suchadministration.

For buccal or sublingual administration, the compositions can betablets, lozenges, or gels.

Parental injections can be formulated for bolus injection or continuousinfusion. The pharmaceutical compositions can be in a form suitable forparenteral injection as a sterile suspension, solution or emulsion inoily or aqueous vehicles, and can contain formulatory agents such assuspending, stabilizing and/or dispersing agents. Pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. Suspensions of the activecompounds can be prepared as oily injection suspensions. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions can contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. The suspension can also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The active compounds can be administered topically and can be formulatedinto a variety of topically administrable compositions, such assolutions, suspensions, lotions, gels, pastes, medicated sticks, balms,creams, and ointments. Such pharmaceutical compositions can containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

Formulations suitable for transdermal administration of the activecompounds can employ transdermal delivery devices and transdermaldelivery patches, and can be lipophilic emulsions or buffered aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches can be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical compounds. Transdermal delivery can beaccomplished by means of iontophoretic patches. Additionally,transdermal patches can provide controlled delivery. The rate ofabsorption can be slowed by using rate-controlling membranes or bytrapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices can be in the form of a bandage comprising a backing member, areservoir containing compounds and carriers, a rate controlling barrierto deliver the compounds to the skin of the subject at a controlled andpredetermined rate over a prolonged period of time, and adhesives tosecure the device to the skin or the eye.

For administration by inhalation, the active compounds can be in a formas an aerosol, a mist, or a powder. Pharmaceutical compositions areconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebuliser, with the use of a suitable propellant,for example, dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compounds and a suitablepowder base such as lactose or starch.

The compounds can also be formulated in rectal compositions such asenemas, rectal gels, rectal foams, rectal aerosols, suppositories, jellysuppositories, or retention enemas, containing conventional suppositorybases such as cocoa butter or other glycerides, as well as syntheticpolymers such as polyvinylpyrrolidone and PEG. In suppository forms ofthe compositions, a low-melting wax such as a mixture of fatty acidglycerides or cocoa butter can be used.

In practicing the methods of treatment or use provided herein,therapeutically-effective amounts of the compounds described herein areadministered in pharmaceutical compositions to a subject having adisease or condition to be treated. In some embodiments, the subject isa mammal such as a human A therapeutically-effective amount can varywidely depending on the severity of the disease, the age and relativehealth of the subject, the potency of the compounds used, and otherfactors. The compounds can be used singly or in combination with one ormore therapeutic agents as components of mixtures.

Pharmaceutical compositions can be formulated using one or morephysiologically-acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compounds intopreparations that can be used pharmaceutically. Formulation can bemodified depending upon the route of administration chosen.Pharmaceutical compositions comprising a compounds described herein canbe manufactured, for example, by mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orcompression processes.

The pharmaceutical compositions can include at least onepharmaceutically acceptable carrier, diluent, or excipient and compoundsdescribed herein as free-base or pharmaceutically-acceptable salt form.The methods and pharmaceutical compositions described herein include theuse crystalline forms (also known as polymorphs), and active metabolitesof these compounds having the same type of activity.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically-acceptable excipients or carriers to form asolid, semi-solid, or liquid composition. Solid compositions include,for example, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include, for example, solutionsin which a compound is dissolved, emulsions comprising a compound, or asolution containing liposomes, micelles, or nanoparticles comprising acompound as disclosed herein. Semi-solid compositions include, forexample, gels, suspensions and creams. The compositions can be in liquidsolutions or suspensions, solid forms suitable for solution orsuspension in a liquid prior to use, or as emulsions. These compositionscan also contain minor amounts of nontoxic, auxiliary substances, suchas wetting or emulsifying agents, pH buffering agents, and otherpharmaceutically-acceptable additives.

Non-limiting examples of dosage forms suitable for use in the inventioninclude feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant,spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension,nanoparticle, microgel, suppository troches, aqueous or oilysuspensions, ointment, patch, lotion, dentifrice, emulsion, creams,drops, dispersible powders or granules, emulsion in hard or soft gelcapsules, syrups, phytoceuticals, nutraceuticals, and any combinationthereof.

Non-limiting examples of pharmaceutically-acceptable excipients suitablefor use in the invention include granulating agents, binding agents,lubricating agents, disintegrating agents, sweetening agents, glidants,anti-adherents, anti-static agents, surfactants, anti-oxidants, gums,coating agents, coloring agents, flavouring agents, coating agents,plasticizers, preservatives, suspending agents, emulsifying agents,anti-microbial agents, plant cellulosic material and spheronizationagents, and any combination thereof.

A composition of the invention can be, for example, an immediate releaseform or a controlled release formulation. An immediate releaseformulation can be formulated to allow the compounds to act rapidly.Non-limiting examples of immediate release formulations include readilydissolvable formulations. A controlled release formulation can be apharmaceutical formulation that has been adapted such that drug releaserates and drug release profiles can be matched to physiological andchronotherapeutic requirements or, alternatively, has been formulated toeffect release of a drug at a programmed rate. Non-limiting examples ofcontrolled release formulations include granules, delayed releasegranules, hydrogels (e.g., of synthetic or natural origin), othergelling agents (e.g., gel-forming dietary fibers), matrix-basedformulations (e.g., formulations comprising a polymeric material havingat least one active ingredient dispersed through), granules within amatrix, polymeric mixtures, and granular masses.

The disclosed compositions can optionally comprise from about 0.001% toabout 0.005% weight by volume pharmaceutically acceptable preservatives.One non-limiting example of a suitable preservative is benzyl alcohol.

In some, a controlled release formulation is a delayed release form. Adelayed release form can be formulated to delay a compound's action foran extended period of time. A delayed release form can be formulated todelay the release of an effective dose of one or more compounds, forexample, for about 4, about 8, about 12, about 16, or about 24 hours.

A controlled release formulation can be a sustained release form. Asustained release form can be formulated to sustain, for example, thecompound's action over an extended period of time. A sustained releaseform can be formulated to provide an effective dose of any compounddescribed herein (e.g., provide a physiologically-effective bloodprofile) over about 4, about 8, about 12, about 16 or about 24 hours.Non-limiting examples of pharmaceutically-acceptable excipients can befound, for example, in Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., PharmaceuticalDosage Forms, Marcel Decker, New York, N.Y., 1980; and PharmaceuticalDosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams& Wilkins1999), each of which is incorporated by reference in itsentirety.

The disclosed methods include administration of a HPTP-β inhibitor or apharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable carrier. The carrier can be selected tominimize any degradation of the active ingredient and to minimize anyadverse side effects in the subject.

In another aspect, the 4 HPTP-β inhibitor or a pharmaceuticallyacceptable salt thereof can be used prophylactically, i.e., as apreventative agent after treatment with an anti-VEGF agent has stopped.The HPTP-β inhibitor or a pharmaceutically acceptable salt thereofherein can be conveniently formulated into pharmaceutical compositionscomposed of one or more pharmaceutically acceptable carriers. See e.g.,Remington's Pharmaceutical Sciences, latest edition, by E.W. Martin MackPub. Co., Easton, Pa., which discloses typical carriers and conventionalmethods of preparing pharmaceutical compositions that can be used inconjunction with the preparation of formulations of the compounddescribed herein and which is incorporated by reference herein. Suchpharmaceutical can be standard carriers for administration ofcompositions to humans and non-humans, including solutions such assterile water, saline, and buffered solutions at physiological pH. Othercompositions can be administered according to standard procedures usedby those skilled in the art. For example, pharmaceutical compositionscan also include one or more additional active ingredients such asantimicrobial agents, anti-inflammatory agents, anesthetics, and thelike.

Non-limiting examples of pharmaceutically-acceptable carriers include,but are not limited to, saline, Ringer's solution and dextrose solution.The pH of the solution can be from about 5 to about 8, and can be fromabout 7 to about 7.5. Further carriers include sustained releasepreparations such as semipermeable matrices of solid hydrophobicpolymers containing the HPTP-β inhibitor or apharmaceutically-acceptable salt thereof, which matrices are in the formof shaped articles, e.g., films, liposomes, microparticles, ormicrocapsules.

The disclosed methods relate to administering the HPTP-β inhibitor or apharmaceutically acceptable salt thereof as part of a pharmaceuticalcomposition. Compositions suitable for topical administration can beused (see, for example, US Patent Application 2005/0059639 includedherein by reference in its entirety). In various embodiments,compositions of the invention can comprise a liquid comprising an activeagent in solution, in suspension, or both. Liquid compositions caninclude gels. In one embodiment, the liquid composition is aqueous.Alternatively, the composition can take form of an ointment. In anotherembodiment, the composition is an in situ gellable aqueous composition.In iteration, the composition is an in situ gellable aqueous solution.Such a composition can comprise a gelling agent in a concentrationeffective to promote gelling upon contact with the eye or lacrimal fluidin the exterior of the eye. Aqueous compositions of the invention haveophthalmically compatible pH and osmolality. The composition cancomprise an ophthalmic depot formulation comprising an active agent forsubconjunctival administration. The microparticles comprising activeagent can be embedded in a biocompatible pharmaceutically acceptablepolymer or a lipid encapsulating agent. The depot formulations may beadapted to release all or substantially all the active material over anextended period of time. The polymer or lipid matrix, if present, may beadapted to degrade sufficiently to be transported from the site ofadministration after release of all or substantially all the activeagent. The depot formulation can be a liquid formulation, comprising apharmaceutical acceptable polymer and a dissolved or dispersed activeagent. Upon injection, the polymer forms a depot at the injections site,e.g. by gelifying or precipitating. The composition can comprise a solidarticle that can be inserted in a suitable location in the eye, such asbetween the eye and eyelid or in the conjuctival sac, where the articlereleases the active agent. Solid articles suitable for implantation inthe eye in such fashion generally comprise polymers and can bebioerodible or non-bioerodible.

Pharmaceutical formulations can include additional carriers, as well asthickeners, diluents, buffers, preservatives, surface active agents andthe like in addition to the compounds disclosed herein. Pharmaceuticalformulations can also include one or more additional active ingredientssuch as antimicrobial agents, anti-inflammatory agents, anesthetics, andthe like.

An excipient can fill a role as simple and direct as being an inertfiller, or an excipient as used herein may be part of a pH stabilizingsystem or coating to insure delivery of the ingredients safely to thestomach. The formulator can also take advantage of the fact thecompounds of the present disclosure have improved cellular potency,pharmacokinetic properties, as well as improved oral bioavailability.

The HPTP-β inhibitor or a pharmaceutically acceptable salt thereof canalso be present in liquids, emulsions, or suspensions for delivery ofactive therapeutic agents in aerosol form to cavities of the body suchas the nose, throat, or bronchial passages. The ratio of HPTP-βinhibitor or a pharmaceutically acceptable salt thereof to the othercompounding agents in these preparations can vary as the dosage formrequires.

Depending on the intended mode of administration, the pharmaceuticalcompositions administered as part of the disclosed methods can be in theform of solid, semi-solid or liquid dosage forms, such as, for example,tablets, suppositories, pills, capsules, powders, liquids, suspensions,lotions, creams, gels, or the like, for example, in unit dosage formsuitable for single administration of a precise dosage. The compositionscan, as noted above, an effective amount of the HPTP-β inhibitor or apharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable carrier and, in addition, can include othermedicinal agents, pharmaceutical agents, carriers, adjuvants, diluents,etc.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. In one embodiment, a compositioncomprising the HPTP-β inhibitor or a pharmaceutically acceptable saltthereof in an amount of approximately 5 mg per 0.1 mL liquid isprepared. The liquid phase comprises sterile water and an appropriateamount of a saccharide or polysaccharide.

Methods of Administration and Treatment Methods.

Pharmaceutical compositions containing compounds described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions can be administered to asubject already suffering from a disease or condition, in an amountsufficient to cure or at least partially arrest the symptoms of thedisease or condition, or to cure, heal, improve, or ameliorate thecondition. Compounds can also be administered to lessen a likelihood ofdeveloping, contracting, or worsening a condition. Amounts effective forthis use can vary based on the severity and course of the disease orcondition, previous therapy, the subject's health status, weight, andresponse to the drugs, and the judgment of the treating physician.

Multiple therapeutic agents can be administered in any order orsimultaneously. If simultaneously, the multiple therapeutic agents canbe provided in a single, unified form, or in multiple forms, forexample, as multiple separate pills. The compounds can be packedtogether or separately, in a single package or in a plurality ofpackages. One or all of the therapeutic agents can be given in multipledoses. If not simultaneous, the timing between the multiple doses mayvary to as much as about a month.

Compounds and compositions of the invention can be packaged as a kit. Insome embodiments, a kit includes written instructions on the use of thecompounds and compositions.

Compounds described herein can be administered before, during, or afterthe occurrence of a disease or condition, and the timing ofadministering the composition containing a compound can vary. Forexample, the compounds can be used as a prophylactic and can beadministered continuously to subjects with a propensity to conditions ordiseases in order to lessen a likelihood of the occurrence of thedisease or condition. The compounds and compositions can be administeredto a subject during or as soon as possible after the onset of thesymptoms. The administration of the compounds can be initiated withinthe first 48 hours of the onset of the symptoms, within the first 24hours of the onset of the symptoms, within the first 6 hours of theonset of the symptoms, or within 3 hours of the onset of the symptoms.The initial administration can be via any route practical, such as byany route described herein using any formulation described herein. Acompound can be administered as soon as is practicable after the onsetof a disease or condition is detected or suspected, and for a length oftime necessary for the treatment of the disease, such as, for example,from about 1 month to about 3 months. The length of treatment can varyfor each subject.

Pharmaceutical compositions described herein can be in unit dosage formssuitable for single administration of precise dosages. In unit dosageform, the formulation is divided into unit doses containing appropriatequantities of one or more compounds. The unit dosage can be in the formof a package containing discrete quantities of the formulation.Non-limiting examples are packaged injectables, vials, or ampoules.Aqueous suspension compositions can be packaged in single-dosenon-reclosable containers. Multiple-dose reclosable containers can beused, for example, in combination with or without a preservative.Formulations for parenteral injection can be presented in unit dosageform, for example, in ampoules, or in multi-dose containers with apreservative.

A compound described herein can be present in a composition in a rangeof from about 1 mg to about 2000 mg; from about 5 mg to about 1000 mg,from about 10 mg to about 25 mg to 500 mg, from about 50 mg to about 250mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg,from about 50 mg to about 100 mg, from about 100 mg to about 150 mg,from about 150 mg to about 200 mg, from about 200 mg to about 250 mg,from about 250 mg to about 300 mg, from about 300 mg to about 350 mg,from about 350 mg to about 400 mg, from about 400 mg to about 450 mg,from about 450 mg to about 500 mg, from about 500 mg to about 550 mg,from about 550 mg to about 600 mg, from about 600 mg to about 650 mg,from about 650 mg to about 700 mg, from about 700 mg to about 750 mg,from about 750 mg to about 800 mg, from about 800 mg to about 850 mg,from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, orfrom about 950 mg to about 1000 mg.

A compound described herein can be present in a composition in an amountof about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg,about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg,about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg,about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg,about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850mg, about 1900 mg, about 1950 mg, or about 2000 mg.

Kits

The present disclosure further relates to kits containing compositionsaccording to Formulation Example 2 for use by medical or other trainedpersonnel, as well as for use by trained subjects for delivery of thedisclosed compositions according to Formulation Example 2 to a subject.In general the disclosed kits comprise:

-   -   A) an aqueous composition as described herein containing from        about 1 mg/mL to about 60 mg/mL of the        4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid; and    -   B) a means for delivering the composition to a subject.

The compositions according to Formulation Example 2can comprise thefollowing concentrations of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid : 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL,15mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22mg/mL, 23 mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29mg/mL, 30 mg/mL, 31 mg/mL, 32 mg/mL, 33 mg/mL, 34 mg/mL, 35 mg/mL, 36mg/mL, 37 mg/mL, 38 mg/mL, 39 mg/mL, 40 mg/mL, 41 mg/mL, 42 mg/mL, 43mg/mL, 44 mg/mL, 45 mg/mL, 46 mg/mL, 47 mg/mL, 48 mg/mL, 49 mg/mL, 50mg/mL,51 mg/mL, 52 mg/mL, 53 mg/mL, 54 mg/mL, 55 mg/mL, 56 mg/mL, 57mg/mL, 58 mg/mL, 59 mg/mL, and 60 mg/mL.

The disclosed compositions according to Formulation Example 2 can beadministered to a subject. Non-limiting examples of routes ofadministration include parenteral delivery, i.e., intravenous,subcutaneous, and intramuscular. Delivery can be by, for example,syringes, needles, infusion pumps, injectors. Syringes and injectors canbe, for example, single-dose, multi-dose, fixed-dose or variable-dose.Examples of injectors include, but are not limited to, pen injectors,auto-injectors, and electronic patch injector systems. One convenientmeans for delivering the disclosed compositions according to FormulationExample 2 is by single use disposable auto injectors. One non-limitingexample is a single use injector configured like the single injectorsold under the Tradename MOLLY™. Non-limiting examples of injectors aredescribed in U.S. Pat. Nos. 7,442,185; 8,038,649; 8,062,255; 8,075,517;8,235,952; 8,277,412; 8,529,510; and 8,551,054.

The kits can comprise suitable components for the administration of acompound of the invention to a subject. In some embodiments a compoundof the invention is present in the kit as a unit dosage form. Forexample, the kit may comprise a delivery device that is capable ofholding a single dose volume of 0.75 mL is capable of delivering 15mg/mL of compound when the concentration of the compound is 20 mg/mL. Assuch, the formulator can provide delivery devices having a higherconcentration of compound and adjust the delivered volume to provide anamount of compound that is less than the amount in the entire solution.In another embodiment the kit comprises a delivery device that containsa sufficient amount of a composition to allow for administration ofmultiple doses from the delivery device.

In some embodiments, a kit of the invention comprises:

-   -   A) a composition for delivering a HPTP-β inhibitor or a        pharmaceutically acceptable salt; and    -   B) a composition for delivering an anti-VEGF agent.

The kits can be modified to fit the dosing regimen prescribed for thesubject being treated. The following is a non-limiting example of a kitfor use with a patient receiving an intravenously delivered compositioncomprising the disclosed compounds and an intravireally administeredanti-VEGF agent. This particular example provides dosing of thedisclosed compounds twice daily for 3 months and for an injection ofranibizumab at week 12.

A. 3 packages, each package containing 4 vials. Each vial comprising asufficient amount of a HPTP-β inhibitor or a pharmaceutically acceptablesalt to provide 2 daily injections of 5 mg of the disclosed compoundsfor 7 days; and

B. a vial of ranibizumab for injection at the end of week 12 whichprovides 0.5 mg of ranibizumab.

The artisan, however, can provide kits that comprise any combination ofelements. In addition, when the disclosed HPTP-β inhibitors or apharmaceutically acceptable salt provided orally, a single containerwith sufficient doses of the disclosed compounds can be supplied withthe kit.

Also included with each kit labels providing instructions for use anddisposal can be included, as well as instructions for use of thecompositions to be delivered. The instructions can be modified from kitto kit to reflect the dosing regime prescribed. The instructiosn candescribe any therapy, compounds, excipients, or method of administrationdescribed herein.

The following are additional non-limiting examples of compositionsaccording to Formulation Example 2 that can comprise the disclosed kits.

One example is a kit comprising:

A) an aqueous composition containing:

-   -   a) 10 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-        yl)thiazol-4-yl]ethyl}-phenylsulfamic acid;    -   b) 62.5 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system, comprising:        -   i) a tonicity agent; and        -   ii) water        -   wherein the tonicity agent is present in an amount such that            the concentration in the final composition is from about 1%            to about 5% weight to volume and the carrier system is            present in an amount such that the concentration of the            4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic            acid has a concentration of 10 mg/mL; and

B) a component for delivering the aqueous composition.

In one non-limiting example, the kit comprises:

A) 1 mL of an aqueous composition containing:

-   -   a) 10 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-        yl)thiazol-4-yl]ethyl}-phenylsulfamic acid;    -   b) 62.5 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) the balance 2% weight to volume of aqueous dextrose; and

B) a component for delivering the aqueous composition;

-   -   wherein the component for delivery is a single use syringe.

In another non-limiting example, the kit comprises:

A) 0.75 mL of an aqueous composition containing

-   -   a) 10 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid;    -   b) 62.5 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) the balance 2% weight to volume of aqueous dextrose; and

B) a component for delivering the aqueous composition;

-   -   wherein the component for delivery is a single use syringe.

One example is a kit comprising:

A) an aqueous composition containing:

-   -   a) 15 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid;    -   b) 93.75 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system, comprising:        -   i) a tonicity agent; and        -   ii) water        -   wherein the tonicity agent is present in an amount such that            the concentration in the final compositons is from about 1%            to about 10% weight to volume and the carrier system is            present in an amount such that the concentration of the            4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic            acid is15 mg/mL; and

B) a component for delivering the aqueous composition.

In one non-limiting example, the kit comprises:

A) 1 mL of an aqueous composition containing:

-   -   a) 15 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid;    -   b) 93.75 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) the balance 2% weight to volume of aqueous dextrose; and

B) a component for delivering the aqueous composition;

-   -   wherein the component for delivery is a single use syringe.

In another non-limiting example, the kit comprises:

A) 0.75 mL of an aqueous composition containing

-   -   a) 15 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid;    -   b) 93.75 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) the balance 2% weight to volume of aqueous dextrose; and

B) a component for delivering the aqueous composition;

-   -   wherein the component for delivery is a single use syringe.

In a further aspect the kits comprising a composition according toFormulation Example 2 is a kit, comprising:

A) an aqueous composition containing:

-   -   a) 20 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid;    -   b) 125 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system, comprising:        -   i) a tonicity agent; and        -   ii) water        -   wherein the tonicity agent is present in an amount such that            the concentration in the final composition is from about 1%            to about 10% weight to volume; and

B) a component for delivering the aqueous composition.

In another aspect the kits comprising a composition according toFormulation Example 2 is a pharmaceutical kit, comprising:

A) a 0.75 mL single dose syringe, the syringe containing a composition,comprising:

-   -   a) 20 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid;    -   b) 125 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system, comprising:        -   i) 2% weight to volume of dextrose of the composition; and        -   ii) water; and

B) instructions for use of the kit.

A further aspect of the compositions according to Formulation Example 2relates to kits which comprise a solid composition for reconstitution.The amount of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamicacid or a pharmaceutically acceptable salt thereof in the container ofdry composition can be in any convenient amount. For example, acontainer comprising 20 mg of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamicacid or a pharmaceutically acceptable salt thereof can have ademarcation line indicating a final volume of 1 mL. The user can thenreconstitute the composition by adding sufficient carrier to create acomposition comprising 20 mg/mL of the compound. The formulator also hasoptions for use according to the instructions. For example, theinstructions can direct the user to withdrawn a sufficient amountaccording to the prescribed dose. If the prescribed dose is 15 mg/mL theuser can withdraw 0.75 mL's of the 20 mg/mL solution for delivery to thesubject. Therefore, instructions for re-constitution can afford the userwith the proper method of reconstitution, as well as the amount ofre-constituted formula to be delivered to a subject.

The following is a non-limiting example of a kit containing a solidcomposition:

A) a solid or dry composition, comprising:

-   -   a) 4-{(S)-2-[(S)-2-(methoxycarb        onylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid or a pharmaceutically acceptable salt thereof; and    -   b) HPβCD;        wherein the ratio of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid to HPβCD is from about 1:4 to about 1:8 and the tonicity        agent is present in an amount such that the re-constituted        formula comprises from about 0.5% to about 10% weight to volume        of the tonicity agent

In another iteration the dry compositions for reconstitution cancomprise:

-   -   a)        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) HPβCD; and    -   c) a tonicity agent;        wherein the ratio of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic        acid to HPβCD is from about 1:4 to about 1:8 and the tonicity        agent is present in an amount such that the re-constituted        formula comprises from about 0.5% to about 10% weight to volume        of the tonicity agent.

A set of instructions can be included in any of the herein describedkits. The instructions can relate to the dosing amount, timing ofdosing, and reconstitution of the composition when the kit contains adry composition, methods of disposal of delivery means and unusedcomposition, and the like.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamicacid can be prepared by the procedure outlined in

Scheme XXIV and describe in Example 25 herein below.

EXAMPLE 334-{(S)-2-[(S)-2-Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (72)

Preparation of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamicacid tert-butyl ester (6): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid, 1,(1.20 g, 4.0 mmol) in THF (20 mL) was added dropwise triethylamine (0.61mL, 4.4 mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol).The reaction mixture was stirred at 0° C. for 20 minutes and filtered.The filtrate was treated with an ether solution of diazomethane (˜16mmol) at 0° C. The reaction mixture was stirred at room temperature for3 hours then concentrated in vacuo. The resulting residue was dissolvedin EtOAc and washed successively with water and brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified over silica(hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product asa slightly yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J=8.7 Hz,2H), 7.39 (d, J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49(s, 1H), 3.25 (dd, J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz,1H), 1.41 (s, 9H).

Preparation of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate (7): To a 0° C.solution of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is addeddropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture wasstirred at 0° C. for 1.5 hours then the reaction was quenched at 0° C.with sat. Na₂CO₃. The mixture is extracted with EtOAc (3× 25 mL) and thecombined organic extracts are washed with brine, dried (Na₂SO₄),filtered and concentrated to obtain 0.400 g of the product which wasused in the next step without further purification. ¹H NMR (300 MHz,CDCl₃) δ 8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8Hz, 1H), 4.80 (q, J=6.3 Hz, 2H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of(S)-2-(4-Nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethanaminehydrobromide (65): Thiophene-2-carbothioamide in acetonitrile (4 vol.with respect to 7) was stirred at 15 to 25° C. for 30 to 60 minutes. Toremove residual sulfur, the resulting mixture was filtered throughCelite® and the reaction flask and filter cake are rinsed withacetonitrile (2×1 vol). The filtrate was then added to the reactorcontaining and (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (0.98 eq) under anitrogen atmosphere. Additional ACN was added and the resulting brightyellow slurry was heated to 80° C. over 6 hours. The reaction mixturewas refluxed for 6 to 16 hours. The reaction mixture was cooled to 65 to70° C. over 1 hour and stirred for an additional 1 to 4 hours. Thereaction mixture was then cooled to 50 to 60° C. over 1 hour. Thereaction mixture was aged for an additional 1 to 2 hours at 50 to 60° C.The reaction mixture was then cooled to 20 to 25° C. over 1 hour. Thereaction mixture was aged for an additional 4 to 16 hours at 20 to 25°C. The resulting slurry was filtered and the filter cake was washed withACN. The wet cake was dried under vacuum at 40 to 45° C. to afford thedesired product.

Preparation of methyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate(68); A solution of (S)-2-[(methoxy-carbonyl)amino]-3-phenylpropanoicacid (66) (1.07 eq.) was added to a reactor containing(S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethanamine (67)(1.0 eq.) under a nitrogen atmosphere.2-Chloro-4,6-dimethoxy-1,3,5-triazine (1.07 eq) was added to the stirredreaction mixture followed by tetrahydrofuran (THF) (ca. 13 vol. withrespect to 67). The temperature was adjusted to 19 to 25° C. andN-methylmorpholine (NMM) (0.4 eq) was added at a rate such that thetemperature was maintained between 20 and 30° C. The reaction mixturewas stirred at 19 to 25° C. for 50 to 70 minutes. Additional NMM (0.4eq) was added at a rate such that the temperature was maintained between20 and 30° C. The resulting reaction mixture was stirred at 19 to 25° C.for 50 to 70 minutes. Additional NMM (0.2 eq) was added at a rate suchthat the temperature was maintained between 20 and 30° C. The resultingreaction mixture was stirred at 19 to 25° C. for 50 to 70 minutes.Additional NMM (1.2 eq) was added at a rate such that the temperaturewas maintained between 20 and 30° C. The resulting reaction mixture wasstirred at 19 to 25° C. for 90 to 120 minutes. The reaction mixture wasfurther stirred at 19 to 25° C. for 2 to 3 hours. A sample of reactionmixture was tested to determined chemical purity. The reaction mixturewas then stirred at 19 to 25° C. for minimum 8 hours. The resultingslurry was filtered and the filter cake washed with THF (2×1 vol,). Thewet cake was added back to the reactor and de-ionized water (40 vol.)was added. Tetrahydrofuran (20 vol.) was added to the stirred reactionmixture and stirring was continued for 4 to 16 hours at 19 to 25° C. Thesolids are collected by filtration. The filter cake was washed with a2:1(v/v) water/THF mixture. The wet cake was further dried under vacuumat room temperature or 40-50° C. for minimum 12 hours to afford thedesired product.

Preparation of methyl((S)-1-(((S)-2-(4-aminophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-y0carbamate(69): To a reactor purged with nitrogen was added methyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate(68), the catalyst, Pd/C (10%) (0.2:1 ratio of catalyst to 68 byweight), and tetrahydrofuran (THF). The reactor was pressurized to 45psi with nitrogen for minimum 5 minutes then depressurized toapproximately 5 psi nitrogen. This procedure was repeated three timesbefore reactor was finally pressurized to 30 to 36 psi with hydrogen.The resulting mixture was stirred for a minimum of 24 hours whilemaintaining the pressure at 30 to 36 psi with hydrogen. The reactor wasthen depressurized and purged with nitrogen for testing of reactioncompletion. The reaction mixture was filtered through a bed of Celite®filter aid to remove the catalyst and the filter cake was washed withTHF. The combined filtrate and washes were concentrated under reducedpressure at 30 to 50° C. to approximately 3 volumes. The reactionmixture was cooled to 19 to 25° C. and methyl t-butyl ether (MTBE) (2.5vol.) was added over 30 minutes. The resulting reaction mixture wasstirred at 19 to 25° C. for 60 to 120 minutes during which time theproduct begins to precipitate. Additional MTBE (9.5 vol.) was added overa period of 60 to 90 minutes. The resulting slurry was aged at 19 to 25°C. for a period of 6 to 16 hours. The solids are collected by filtrationand the filter cake was washed with MTBE. The wet cake was then driedunder vacuum at room temperature or 40-50° C. to afford the desiredproduct.

Preparation of trimethylammonium(4-((S)-2-((S)-2-((methoxycarbonyl)amino)-3-phenylpropanamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenyl)sulfamate(70):((S)-1-(((S)-2-(4-aminophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate(69), trimethylamine sulfur trioxide complex (1.71 eq.) andtetrahydrofuran (THF) (7.1 vol.) were added to a reactor purged withnitrogen. The reaction mixture was stirred and triethylamine (0.106 eq.)was added at 19 to 25° C. The stirred reaction mixture was warmed to 35to 40° C. and stirred for 4 to 8 hours. The reaction mixture was cooledto 19 to 25° C. and stirring was continued for 1 to 2 hours. Thereaction mixture was filtered and the filter cake was washed with THF.The combined filtrate and washes are added to a stirred reactorcontaining methyl t-butyl ether (MTBE) (10 vol.) over a minimum of 2hour period. On completion of the addition, the reaction mixture wasstirred at 19 to 25° C. for 4 to 16 hours. The solids are collected byfiltration and the wet cake was washed with MTBE. The wet cake was driedunder vacuum at 20 to 25° C. for 2 hours to afford the desired product.

Preparation of sodium(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamate(71): trimethyl-ammonium(4-((S)-2-((S)-2-((methoxycarbonyl)amino)-3-phenylpropanamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)-phenyl)sulfamate(70) was added to a stirred reactor containing methanol (MeOH) (4.87vol.) and sodium methoxide (25% solution in MeOH) (0.093 eq.). Sodiummethoxide (25% solution in MeOH) (1.08 eq.) was added over 5 minuteswhile maintaining the temperature at 19 to 25° C. The resulting mixturewas stirred at 19-25° C. for 30 to 60 minutes then 2 portions of sodiummethoxide (25% solution in MeOH) (0.14 eq. and 0.07 eq.) are added over30 minutes while maintaining the temperature at 19 to 25° C. Theresulting mixture was stirred for 30 to 60 minutes while maintaining thetemperature at 19 to 25° C. The reaction mixture was then filtered andthe filter cake washed with methanol (MeOH). The filtrates and cakewashes are concentrated under reduced pressure at 30 to 40° C. toapproximately 8 volumes. The reaction mixture was cooled to 19 to 25° C.and methyl t-butyl ether (10 vol) was then added. The reaction mixturewas then stirred for 15 to 20 minutes. The resulting solids are isolatedby filtration and the filter cake was washed with MTBE. The wet cake wasdried under vacuum at room temperature or 35-40° C. for a minimum of 2hours to afford the desired product.

Preparation of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (72): sodium(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate71) (97.0 gm, 0.16 mol) was slowly added to distilled water (1.0 L) andacetone (200 mL) in a three-neck 5-L round bottom flask equipped with anoverhead mechanical stirrer, a thermometer and an addition funnel atambient temperature. To the resulting suspension 85% H₃PO₄ (20.33 g, 1.1eq.) diluted with water (100 mL) was slowly added through the additionfunnel over 15 minutes. No apparent temperature change was observed. Aconsiderable amount of a free-flowing suspension formed in 10-15 minutesafter the addition was complete. The suspension was stirred at ambienttemperature for 2 hours and filtered. The solid cake was rinsed with 20%acetone in water (2×50 mL). The solid was removed and dried under vacuumto afford 88.05 g (93.8% yield) of the desired product as a light-yellowsolid which HPLC analysis indicated had a purity of 99.26%. ¹H (CD₃OD):δ 7.61-7.56 (m, 2H), 7.25-7.01 (m, 10H), 6.75 (s, 1H), 5.24-5.21 (q, 1H,J=7.2 Hz), 4.38 (t, 1H, J=7.2 Hz), 3.60 (s, 3H), 3.23-3.14 (m, 1H),3.08-3.00 (m, 2H), 2.87-2.80 (m, 1H).

Formulation Example 3

This formulation example relates to compositions comprising4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenyl-sulfamic acid having the formula:

and pharmaceutically acceptable salts thereof.

Formulation Example 3 comprises:

-   -   a)        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) a solubilizing system; and    -   c) a carrier system.

The compositions of Formulation Example 3 are formulated to deliver anamount of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid in the free acid form. For example, a composition which comprises10 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid can have either 10 mg/mL of the free acid or an amount of apharmaceutically acceptable salt in an amount sufficient to deliver 10mg/mL of the free acid. As an example, a composition formulated todeliver 10 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid can comprise either 10 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or alternatively 10.4 mg/mL of the sodium salt, (sodium4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamate).Therefore, a composition which delivers from about 10 mg/mL to about 100mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid can comprise an amount of pharmaceutically acceptable salt thereofto deliver from about 10 mg/mL to about 100 mg/mL of the compound

Therefore, when a composition according to Formulation Example 3comprises an amount of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid per mL, it is understood that this amount is the amount of freeacid that is delivered and if a salt form of the compound is used in thecomposition, the amount of the salt form can therefore reflect thedifference in molecular weight between the free acid and the salt form.The following example demonstrates this equivalency.

A composition delivering 10 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid, comprises:

-   -   a) 10 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamic        acid; or about 10.4 mg/mL of sodium        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamate;        or about 10.3 mg/mL, of ammonium        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamate,        and the like;    -   b) an amount of 2-hydroxypropyl-β-cyclodextrin as defined        herein; and    -   c) a carrier system.

The disclosed compositions according to Formulation Example 3 accordingto Formulation Example 3 comprise from about 10 mg/mL to about 100 mg/mLof the4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof.

In one aspect the disclosed compositions according to FormulationExample 3 comprise from about 20 mg/mL to about 100 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In one embodiment,the composition comprises from about 15 mg/mL to about 60 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In anotherembodiment, the composition comprises from about 40 mg/mL to about 90mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}-phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In a furtherembodiment, the composition comprises from about 10 mg/mL to about 30mg/mL of4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}-phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In a still furtherembodiment, the composition comprises from about 40 mg/mL to about 80mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonyl-lamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In a yet furtherembodiment the composition comprises from about 10 mg/mL to about 20mg/mL weight by volume of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In a still yetfurther embodiment, the composition comprises from about 60 mg/mL toabout 90 mg/mL weight by volume of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenyl-sulfamicacid or a pharmaceutically acceptable salt thereof. In still anotherembodiment, the composition comprises from about 50 mg/mL to about 100mg/mL weight by volume of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenyl-sulfamicacid or a pharmaceutically acceptable salt thereof.

Particular embodiments of the disclosed compositions according toFormulation Example 3, comprise 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL 12 mg/mL,13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20mg/mL, 21 mg/mL, 22 mg/mL, 23 mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27mg/mL, 28 mg/mL, 29 mg/mL, 30 mg/mL, 31 mg/mL 32 mg/mL, 33 mg/mL, 34mg/mL, 35 mg/mL, 36 mg/mL, 37 mg/mL, 38 mg/mL, 39 mg/mL, 40 mg/mL, 41mg/mL 42 mg/mL, 43 mg/mL, 44 mg/mL, 45 mg/mL, 46 mg/mL, 47 mg/mL, 48mg/mL, 49 mg/mL, 50 mg/mL, 51 mg/mL 52 mg/mL, 53 mg/mL, 54 mg/mL, 55mg/mL, 56 mg/mL, 57 mg/mL, 58 mg/mL, 59 mg/mL, 60 mg/mL, 61 mg/mL 62mg/mL, 63 mg/mL, 64 mg/mL, 65 mg/mL, 66 mg/mL, 67 mg/mL, 68 mg/mL, 69mg/mL,70 mg/mL, 71 mg/mL 72 mg/mL, 73 mg/mL, 74 mg/mL, 75 mg/mL, 76mg/mL, 77 mg/mL, 78 mg/mL, 79 mg/mL, 80 mg/mL, 81 mg/mL 82 mg/mL, 83mg/mL, 84 mg/mL, 85 mg/mL, 86 mg/mL, 87 mg/mL, 88 mg/mL, 89 mg/mL, 90mg/mL, 91 mg/mL 92 mg/mL, 93 mg/mL, 94 mg/mL, 95 mg/mL, 96 mg/mL, 97mg/mL, 98 mg/mL, 99 mg/mL, and 100 mg/mL, about 1 mg/mL, about 2 mg/mL,about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mLabout 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20 mg/mL,about 21 mg/mL about 22 mg/mL, about 23 mg/mL, about 24 mg/mL, about 25mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29 mg/mL,about 30 mg/mL, about 31 mg/mL, about 32 mg/mL, about 33 mg/mL, about 34mg/mL, about 35 mg/mL, about 36 mg/mL, about 37 mg/mL, about 38 mg/mL,about 39 mg/mL, about 40 mg/mL, about 41 mg/mL, about 42 mg/mL, about 43mg/mL, about 44 mg/mL, about 45 mg/mL, about 46 mg/mL, about 47 mg/mL,about 48 mg/mL, about 49 mg/mL, about 50 mg/mL, about 51 mg/mL, about 52mg/mL, about 53 mg/mL, about 54 mg/mL, about 55 mg/mL, about 56 mg/mL,about 57 mg/mL, about 58 mg/mL, about 59 mg/mL, about 60 mg/mL, about 61mg/mL, about 62 mg/mL, about 63 mg/mL, about 64 mg/mL, about 65 mg/mL,about 66 mg/mL, about 67 mg/mL, about 68 mg/mL, about 69 mg/mL, about 70mg/mL, about 71 mg/mL, about 72 mg/mL, about 73 mg/mL, about 74 mg/mL,about 75 mg/mL, about 76 mg/mL, about 77 mg/mL, about 78 mg/mL, about 79mg/mL, about 80 mg/mL, about 81 mg/mL, about 82 mg/mL, about 83 mg/mL,about 84 mg/mL, about 85 mg/mL, about 86 mg/mL, about 87 mg/mL, about 88mg/mL, about 89 mg/mL, about 90 mg/mL, about 91 mg/mL, about 92 mg/mL,about 93 mg/mL, about 94 mg/mL, about 95 mg/mL, about 96 mg/mL, about 97mg/mL, about 98 mg/mL, about 99 mg/mL, and about 100 mg/mL of a compounddisclosed herein, for example,4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid.

Solubilizing Systems

In one embodiment, a formulation disclosed herein can comprise a ratioof about 20 parts of a compound herein or a pharmaceutically acceptablesalt thereof to about 1 part solubilizing system (about 20 : about 1),to about 1 part of the compound herein or a pharmaceutically acceptablesalt thereof to about 20 parts solubilizing system (about 1 : about 20).For example, a formulation containing about 100 mg of a compound hereinor a pharmaceutically acceptable salt thereof can contain from about 5mg to about 2000 mg of a solubilizing agent, such as a cyclodextrin. Inanother embodiment, the ratio can be based on number, or moles, orcompound compared to number, or moles, of solubilizing system.

The disclosed solubilizing systems can comprise cyclodextrins:β-cyclodextrin, β-cyclodextrin and β-cyclodextrin and derivativesthereof. Non-limiting examples of cyclodextrin derivatives includesmethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutylether-(3-cyclodextrin sodium salt, and 2-hydroxypropyl-β-cyclodextirn.

The following are non-limiting examples of ratios of a compound hereinand a solubilizing agent, such as a cyclodextrin. The following examplesalternatively describe the ratio of a solubilizing agent, such as acyclodextrin, and a compound herein. The ratio can be: about 20 : about1; about 19.9: about 1; about 19.8 : about 1; about 19.7: about 1; about19.6 : about 1; about 19.5 : about 1; about 19.4 : about 1; about 19.3 :about 1; about 19.2 : about 1; about 19.1 : about 1; about 19 : about 1;about 18.9 : about 1; about 18.8 : about 1; about 18.7 : about 1; about18.6 : about 1; about 18.5 : about 1; about 18.4 : about 1; about 18.3 :about 1; about 18.2 : about 1; about 18.1 : about 1; about 18 : about 1;about 17.9 : about 1; about 17.8 : about 1; about 17.7 : about 1; about17.6 : about 1; about 17.5 : about 1; about 17.4: about 1; about 17.3 :about 1; about 17.2: about 1; about 17.1 : about 1; about 17 : about 1;about 16.9 : about 1; about 16.8 : about 1; about 16.7 : about 1; about16.6 : about 1; about 16.5 : about 1; about 16.4 : about 1; about 16.3 :about 1; about 16.2 : about 1; about 16.1 : about 1; about 16 : about 1;about 15.9 : about 1; about 15.8 : about 1; about 15.7 : about 1; about15.6: about 1; about 15.5 : about 1; about 15.4 : about 1; about 15.3 :about 1; about 15.2 : about 1; about 15.1 : about 1; about 15 : about 1;about 14.9 : about 1; about 14.8 : about 1; about 14.7 : about 1; about14.6: about 1; about 14.5 : about 1; about 14.4 : about 1; about 14.3 :about 1; about 14.2 : about 1; about 14.1 : about 1; about 14 : about 1;about 13.9 : about 1; about 13.8 : about 1; about 13.7 : about 1; about13.6 : about 1; about 13.5 : about 1; about 13.4 : about 1; about 13.3 :about 1; about 13.2 : about 1; about 13.1 : about 1; about 13 : about 1;about 12.9 : about 1; about 12.8 : about 1; about 12.7 : about 1; about12.6: about 1; about 12.5 : about 1; about 12.4 : about 1; about 12.3 :about 1; about 12.2 : about 1; about 12.1 : about 1; about 12 : about 1;about 11.9 : about 1; about 11.8 : about 1; about 11.7 : about 1; about11.6: about 1; about 11.5 : about 1; about 11.4 : about 1; about 11.3 :about 1; about 11.2: about 1; about 11.1 : about 1; about 11 : about 1;about 10.9 : about 1; about 10.8 : about 1; about 10.7 : about 1; about10.6 : about 1; about 10.5 : about 1; about 10.4 : about 1; about 10.3 :about 1; about 10.2 : about 1; about 10.1 : about 1; about 10 : about 1;about 9.9 : about 1; about 9.8 : about 1; about 9.7 : about 1; about 9.6: about 1; about 9.5 : about 1; about 9.4 : about 1; about 9.3 : about1; about 9.2 : about 1; about 9.1 : about 1; about 9 : about 1; about8.9 : about 1; about 8.8 : about 1; about 8.7 : about 1; about 8.6 :about 1; about 8.5 : about 1; about 8.4 : about 1; about 8.3 : about 1;about 8.2 : about 1; about 8.1 : about 1; about 8 : about 1; about 7.9 :about 1; about 7.8 : about 1; about 7.7 : about 1; about 7.6 : about 1;about 7.5 : about 1; about 7.4 : about 1; about 7.3 : about 1; about 7.2: about 1; about 7.1 : about 1; about 7 : about 1; about 6.9 : about 1;about 6.8 : about 1; about 6.7 : about 1; about 6.6 : about 1; about 6.5: about 1; about 6.4 : about 1; about 6.3 : about 1; about 6.2 : about1; about 6.1 : about 1; about 6 : about 1; about 5.9 : about 1; about5.8 : about 1; about 5.7 : about 1; about 5.6 : about 1; about 5.5 :about 1; about 5.4 : about 1; about 5.3 : about 1; about 5.2 : about 1;about 5.1 : about 1; about 5 : about 1; about 4.9 : about 1; about 4.8 :about 1; about 4.7 : about 1; about 4.6 : about 1; about 4.5 : about 1;about 4.4 : about 1; about 4.3 : about 1; about 4.2 : about 1; about 4.1: about 1; about 4 : about 1; about 3.9 : about 1; about 3.8 : about 1;about 3.7 : about 1; about 3.6 : about 1; about 3.5 : about 1; about 3.4: about 1; about 3.3 : about 1; about 3.2 : about 1; about 3.1 : about1; about 3 : about 1; about 2.9 : about 1; about 2.8 : about 1; about2.7 : about 1; about 2.6 : about 1; about 2.5 : about 1; about 2.4 :about 1; about 2.3 : about 1; about 2.2 : about 1; about 2.1 : about 1;about 2 : about 1; about 1.9 : about 1; about 1.8 : about 1; about 1.7 :about 1; about 1.6 : about 1; about 1.5 : about 1; about 1.4 : about 1;about 1.3 : about 1; about 1.2 : about 1; about 1.1 : about 1; or about1 : about 1.

As such, the compositions can comprise an amount of HPβCD suitable forachieving the desired properties of the composition, i. e. ,concentration of4-{(S)-2-[(S)-2-(methoxycarbonyl-amino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid, the desired viscosity, the desired osmolarity and the like. Theamount of HPβCD can vary depending upon the amount of4-{(8)-2-[(8)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid the formulator desires to deliver in a single dose.

Carrier System

The disclosed compositions according to Formulation Example 3 comprisefrom about 1.5% to about 90% weight by volume of a carrier system. Theamount of carrier system present is based upon several different factorsor choices made by the formulator, for example, the final concentrationof the compound and the amount of solubilizing agent.

The following is a non-limiting example of a composition comprising 60mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}-phenylsulfamicacid:

-   -   a) 60 mg of the        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamic        acid ;    -   b) 5 mg of 2-hydroxypropyl-beta-cyclodextrin; and    -   c) the balance a carrier system to a volume of 1 mL.

In one aspect, the carrier system comprises:

-   -   i) one or more tonicity agents; and    -   ii) water.

Non-limiting examples of tonicity agents include dextrose, mannitol andglycerin. The formulator can utilize more than one tonicity agent whenformulating the disclosed compositions according to Formulation Example3. The tonicity agent can comprise from about 0.5% to about 5% weight byvolume of the final composition. In non-limiting examples, whenpreparing the final composition, the tonicity agent may be combined with4-{(S)-2-[(S)-2-(methoxycarbonyl-amino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid before mixing with the carrier system. Alternately, whenreconstituting the final composition the formulator can use commerciallyavailable solutions containing a tonicity agent, for example, 5%Dextrose Injection, USP.

The osmolarity of the disclosed compositions according to FormulationExample 3 can be within any range chosen by the formulator. In oneaspect the osmolarity is from about 250 to about 350 mOsm/L. In oneembodiment of this aspect of the disclosed osmolarity is from about 270to about 310 mOsm/L.

The pH of the disclosed compositions according to Formulation Example 3can be from about 6 to about 8. If the pH is outside the range desiredby the formulator, the pH can be adjusted by using sufficientpharmaceutically acceptable acids and bases.

One aspect of the disclosed compositions according to FormulationExample 3 relates to compositions comprising4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or pharmaceutically acceptable salts thereof.

One embodiment of this aspect of the disclosed compositions according toFormulation Example 3 comprises:

-   -   a) from about 42 mg/mL to about 48 mg/mL of the        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 4.2 mg/mL to about 4.8 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 3 comprises:

-   -   a) about 45 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 4.5 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 45 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 45 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

Another embodiment of this aspect of the disclosed compositionsaccording to Formulation Example 3 comprises:

-   -   a) from about 55 mg/mL to about 65 mg/mL of the        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 110 mg/mL to about 6 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 3 comprises:

-   -   a) about 60 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 600 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 60 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 60 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

A further embodiment of this aspect of the disclosed compositionsaccording to Formulation Example 3 comprises:

-   -   a) from about 85 mg/mL to about 95 mg/mL of the        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 20 mg/mL to about 30 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 3 comprises:

-   -   a) about 90 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 1000 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 90 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 500 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

Formulation Example 4

This formulation example relates to compositions comprising4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid having the formula:

and pharmaceutically acceptable salts thereof.

Formulation Example 4 comprises:

-   -   a) 4-{(S)-2-[(S)-2-(methoxycarb        onylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) a solubilizing system; and    -   c) a carrier system.

The compositions of Formulation Example 4 are formulated to deliver anamount of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid in the free acid form. For example, a composition which comprises10 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid can have either 10 mg/mL of the free acid or an amount of apharmaceutically acceptable salt in an amount sufficient to deliver 10mg/mL of the free acid. As an example, a composition formulated todeliver 10 mg/mL of4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid can comprise either 10 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or alternatively 10.4 mg/mL of the sodium salt, (sodium4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamate).Therefore, a composition which delivers from about 0.1 mg/mL to about 90mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid can comprise an amount of pharmaceutically acceptable salt thereofto deliver from about 0.1 mg/mL to about 90 mg/mL of the compound

Therefore, when a composition according to Formulation Example 4comprises an amount of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid per mL, it is understood that this amount is the amount of freeacid that is delivered and if a salt form of the compound is used in thecomposition, the amount of the salt form can therefore reflect thedifference in molecular weight between the free acid and the salt form.The following example demonstrates this equivalency.

A composition delivering 10 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid, comprises:

-   -   a) 10 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid; or about 10.4 mg/mL of sodium        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamate;        or about 10.3 mg/mL, of ammonium        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamate,        and the like;    -   b) an amount of 2-hydroxypropyl-β-cyclodextrin as defined        herein; and    -   c) a carrier system.

The disclosed compositions according to Formulation Example 4 accordingto Formulation Example 4 comprise from about 10 mg/mL to about 90 mg/mLof the4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenyl-sulfamicacid or a pharmaceutically acceptable salt thereof.

In one aspect the disclosed compositions according to FormulationExample 4 comprise from about 20 mg/mL to about 100 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In one embodiment,the composition comprises from about 15 mg/mL to about 60 mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In anotherembodiment, the composition comprises from about 40 mg/mL to about 90mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In a furtherembodiment, the composition comprises from about 10 mg/mL to about 30mg/mL of4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In a still furtherembodiment, the composition comprises from about 40 mg/mL to about 80mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonyl-lamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In a yet furtherembodiment the composition comprises from about 10 mg/mL to about 20mg/mL weight by volume of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. In a still yetfurther embodiment, the composition comprises from about 60 mg/mL toabout 90 mg/mL weight by volume of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenyl-sulfamicacid or a pharmaceutically acceptable salt thereof. In still anotherembodiment, the composition comprises from about 50 mg/mL to about 80mg/mL weight by volume of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenyl-sulfamicacid or a pharmaceutically acceptable salt thereof.

Particular embodiments of the disclosed compositions according toFormulation Example 4, comprise 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL 12 mg/mL,13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20mg/mL, 21 mg/mL, 22 mg/mL, 23 mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27mg/mL, 28 mg/mL, 29 mg/mL, 30 mg/mL, 31 mg/mL 32 mg/mL, 33 mg/mL, 34mg/mL, 35 mg/mL, 36 mg/mL, 37 mg/mL, 38 mg/mL, 39 mg/mL, 40 mg/mL, 41mg/mL 42 mg/mL, 43 mg/mL, 44 mg/mL, 45 mg/mL, 46 mg/mL, 47 mg/mL, 48mg/mL, 49 mg/mL, 50 mg/mL, 51 mg/mL 52 mg/mL, 53 mg/mL, 54 mg/mL, 55mg/mL, 56 mg/mL, 57 mg/mL, 58 mg/mL, 59 mg/mL, 60 mg/mL, 61 mg/mL 62mg/mL, 63 mg/mL, 64 mg/mL, 65 mg/mL, 66 mg/mL, 67 mg/mL, 68 mg/mL, 69mg/mL,70 mg/mL, 71 mg/mL 72 mg/mL, 73 mg/mL, 74 mg/mL, 75 mg/mL, 76mg/mL, 77 mg/mL, 78 mg/mL, 79 mg/mL, 80 mg/mL, 81 mg/mL 82 mg/mL, 83mg/mL, 84 mg/mL, 85 mg/mL, 86 mg/mL, 87 mg/mL, 88 mg/mL, 89 mg/mL, and90 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL,about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9mg/mL, about 10 mg/mL, about 11 mg/mL about 12 mg/mL, about 13 mg/mL,about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL about 22 mg/mL,about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27mg/mL, about 28 mg/mL, about 29 mg/mL, about 30 mg/mL, about 31 mg/mL,about 32 mg/mL, about 33 mg/mL, about 34 mg/mL, about 35 mg/mL, about 36mg/mL, about 37 mg/mL, about 38 mg/mL, about 39 mg/mL, about 40 mg/mL,about 41 mg/mL, about 42 mg/mL, about 43 mg/mL, about 44 mg/mL, about 45mg/mL, about 46 mg/mL, about 47 mg/mL, about 48 mg/mL, about 49 mg/mL,about 50 mg/mL, about 51 mg/mL, about 52 mg/mL, about 53 mg/mL, about 54mg/mL, about 55 mg/mL, about 56 mg/mL, about 57 mg/mL, about 58 mg/mL,about 59 mg/mL, about 60 mg/mL, about 61 mg/mL, about 62 mg/mL, about 63mg/mL, about 64 mg/mL, about 65 mg/mL, about 66 mg/mL, about 67 mg/mL,about 68 mg/mL, about 69 mg/mL, about 70 mg/mL, about 71 mg/mL, about 72mg/mL, about 73 mg/mL, about 74 mg/mL, about 75 mg/mL, about 76 mg/mL,about 77 mg/mL, about 78 mg/mL, about 79 mg/mL, about 80 mg/mL, about 81mg/mL, about 82 mg/mL, about 83 mg/mL, about 84 mg/mL, about 85 mg/mL,about 86 mg/mL, about 87 mg/mL, about 88 mg/mL, about 89 mg/mL, andabout 90 mg/mL of a compound herein, such as4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid.

Solubilizing Systems

In one embodiment, the disclosed compositions according to FormulationExample 4 can comprise from a ratio of about 20 parts of the compoundherein or a pharmaceutically acceptable salt thereof to about 1 partsolubilizing system (about 20 : about 1) to about 1 part of the compoundherein or a pharmaceutically acceptable salt thereof to about 20 partssolubilizing system (about 1 : about 20). The disclosed solubilizingsystems can comprise cyclodextrins, non-limimting examples of whichinclude: β-cyclodextrin, β-cyclodextrin and β-cyclodextrin andderivatives thereof. Non-limiting examples of cyclodextrin derivativesincludes methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin,sulfobutyl ether-β-cyclodextrin sodium salt, and2-hydroxypropyl-β-cyclodextrin.

The formulator can adjust the ratios of the compound to fill3CD basedupon composition parameters, for example, choice and amount of atonicity agent and pH. Suitable ratios are described above. As such, thecompositions can comprise an amount of solubilizing system suitable forachieving the desired properties of the composition, i. e. ,concentration of compound, the desired viscosity, and the desiredosmolarity. The amount of HPβCD can vary depending upon the amount ofcompound that the formulator desires to deliver in a single dose.

Carrier System

The disclosed compositions according to Formulation Example 4 cancomprise from about 1.5% to about 90% weight by volume of a carriersystem. The amount of carrier system present is based upon severaldifferent factors or choices made by the formulator, for example, thefinal concentration of the compound and the amount of solubilizingagent.

The following is a non-limiting example of a composition comprising 60mg/mL of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid:

-   -   a) 60 mg of the        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic        acid ;    -   b) 360 mg of 2-hydroxypropyl-beta-cyclodextrin; and    -   c) the balance a carrier system to a volume of 1 mL.

In one aspect, the carrier system comprises:

-   -   i) one or more tonicity agents; and    -   ii) water.

Non-limiting examples of tonicity agents include dextrose, mannitol andglycerin. The formulator can utilize more than one tonicity agent whenformulating the disclosed compositions according to Formulation Example4. The tonicity agent can comprise from about 0.5% to about 5% weight byvolume of the final composition. In non-limiting examples, whenpreparing the final composition, the tonicity agent may be combined with4-{(S)-2-[(S)-2-(methoxycarbonyl-amino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid before mixing with the carrier system. Alternately, whenreconstituting the final composition the formulator can use commerciallyavailable solutions containing a tonicity agent, for example, 5%Dextrose Injection.

The osmolarity of the disclosed compositions according to FormulationExample 4 can be within any range chosen by the formulator. In oneaspect the osmolarity is from about 250 to about 350 mOsm/L. In oneembodiment of this aspect of the disclosed osmolarity is from about 270to about 310 mOsm/L.

The pH of the disclosed compositions according to Formulation Example 4can be from about 6 to about 8. If the pH is outside the range desiredby the formulator, the pH can be adjusted by using sufficientpharmaceutically acceptable acids and bases.

One aspect of the disclosed compositions according to FormulationExample 4 relates to compositions comprising4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or pharmaceutically acceptable salts thereof.

One embodiment of this aspect of the disclosed compositions according to

Formulation Example 4 comprises:

-   -   a) from about 40 mg/mL to about 45 mg/mL of the        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 120 mg/mL to about 5.2 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 4 comprises:

-   -   a) about 40 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) about 240 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 40 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic        acid;    -   b) 240 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

Another embodiment of this aspect of the disclosed compositionsaccording to Formulation Example 4 comprises:

-   -   a) from about 55 mg/mL to about 65 mg/mL of the        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 5.5 mg/mL to about 650 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 4 comprises:

-   -   a) about 60 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylkpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamic        acid;    -   b) about 30 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 60 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamic        acid;    -   b) 30 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

A further embodiment of this aspect of the disclosed compositionsaccording to Formulation Example 4 comprises:

-   -   a) from about 70 mg/mL to about 77 mg/mL of the        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamic        acid or a pharmaceutically acceptable salt thereof;    -   b) from about 20 mg/mL to about 1000 mg/mL of        2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

A non-limiting iteration of this embodiment of the disclosedcompositions according to Formulation Example 4 comprises:

-   -   a) about 74 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamic        acid;    -   b) about 225 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system.

One specific example of a composition according to this iterationcomprises:

-   -   a) 74 mg/mL of        4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenylsulfamic        acid;    -   b) 225 mg/mL of 2-hydroxypropyl-β-cyclodextrin; and    -   c) a carrier system containing        -   i) 2% weight to volume of the composition dextrose; and        -   ii) water.

4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-ethyl}phenylsulfamicacid can be prepared by the procedure outlined in Scheme XXV anddescribed in Example 34 herein below.

EXAMPLE 344-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamicacid (75)

Preparation of Methyl(S)-1-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-1-oxo-3-phenylpropan-2-ylcarbamate(73): To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine (3) (307 g, 82%, 1.1 mol),(S)-(2-methoxycarbonylamino)-3-phenylpropionic acid (333 g, 89%, 1.33mol, 1.2 eq) and 1-hydroxybenzotriazole (HOBt) (180 g, 1.33 mol, 1.2 eq)in DMF (5 L) at 0° C., was added1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDCI) (255 g, 1.33 mol,1.2 eq) followed by diisopropylamine (285 g, 2.2 mol, 2 eq). The mixturewas stirred at 0° C. for 30 minutes then at room temperature overnight.The reaction mixture was diluted with water (20 L) and extracted withEtOAc (30 L x 3). The combined organic phase was washed with 1 N aqueousHCl, 5% aqueous NaHCO₃, brine and dried over Na₂SO₄. The solvent wasremoved in vacuo and the crude product was washed with a small amount ofEtOAc to afford 245 g of the desired product with 94% HPLC purity.Yield: 56%. LC/MS (M+1): 483; ¹H NMR (300 MHz, CD₃OD): δ 8.14-8.11 (d,2H, J=8.4 Hz), 7.50-7.47 (d, 2H, J=8.4 Hz), 7.20-7.17 (m, 5H), 7.03 (s,1H), 5.52-5.47 (m, 1H), 4.35-4.30 (t, 1H, J=7.8 Hz), 3.67-3.54 (m, 4H),3.25-3.17 (m, 1H), 3.02-2.95 (m, 1H), 2.81-2.74 (m, 3H), 1.31-1.26 (t,3H, J=7.5 Hz).

Preparation of Methyl(S)-1-((S)-2-(4-aminophenyl)-1-(4-ethylthiazol-2-yl)ethyl-amino)-1-oxo-3-phenylpropan-2-ylcarbamate(74): Methyl(S)-1-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-1-oxo-3-phenylpropan-2-ylcarbamate(73) (220 g, 0.45 mol) was dissolved in 4.5 L of ethanol. FeCl₃ (15.0 g,0.09 mol, 0.2 equiv.) and activated carbon (96.8 g) were added to theabove solution. The resulting mixture was then refluxed while hydratedhydrazine (440 mL, 7.04 mol) was added dropwise during 1 h. The mixturewas refluxed for another 2 h and then cooled down to rt. The activatedcarbon was filtered. Filtrate was concentrated under reduced pressure,diluted with 1 L water and extracted with ethyl acetate, washed withbrine, dried over Na₂SO₄. The combined organic layer was concentratedand washed with ethyl ether to afford 10 as off-white solid (163 g,yield: 78.6%). LC/MS (M+1): 453; H NMR (300 MHz, CD₃OD) δ: 7.21-6.98 (m,10H), 5.40-5.38 (t, 1H, J=7.5 Hz), 4.38-4.33 (t, 1H, J=7 .5 Hz), 3.70(s, 3H), 3.24-3.22 (m, 1H), 3.11-3.01 (m, 2H), 2.81-2.72 (m, 3H),1.32-1.26 (t, 3H, J=7.5 Hz). HPLC: 96.5%.

Preparation of4-((S)-2-(4-ethylthiazol-2-yl)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamido)ethyl)phenylsulfamicacid (75): Methyl(S)-14(S)-2-(4-aminophenyl)-1-(4-ethylthiazol-2-yl)ethylamino)-1-oxo-3-phenylpropan-2-ylcarbamate(74) (123 g, 0.272 mol) and N-methylmorpholine (50 g, 0.495 mol) weredissolved in 1.1 L of THF. Me₃NSO₃ complex (58 g, 0.417 mol) was addedin one portion. The resulting mixture was warmed up to 50° C. for 3hours and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (DCM/MeOH=20/1 toDCM/MeOH=10/1) to give the desired product 11 (150 g, yield: 104%),which contained a small amount of Me₃N and MeOSO₃H. LC/MS (M−1): 531; HNMR (300 MHz, CD₃OD) δ: 7.21-6.99 (m, 10H), 5.39-5.34 (t, 1H, J=6.0 Hz),4.39-4.34 (t, 1H, J=8.1 Hz), 3.61 (s, 3H), 3.25-3.23 (m, 1H), 3.10-3.00(m, 2H), 2.81-2.74 (m, 3H), 1.31-1.26 (t, 3H, J=7.2 Hz); HPLC: 98.1%.

Preparation of sodium4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl-amino)-3-phenyl-propanamido]ethyl}phenylsulfamate(76): To a solution of4-((S)-2-(4-ethylthiazol-2-yl)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamido)ethyl)-phenylsulfamicacid (75) (150 g, 0.272 mmol) in methanol (1.2 L) was added 50% NaOH(11.3 g, 0.272 mol, 1.0 equiv.) at room temperature. The resultingmixture was stirred at rt for 30 min and then concentrated under reducedpressure to give the crude product, which contained a small amount ofMe₃N and MeOSO₃Na. To a stirred slurry of the crude product (75 g) inH₂O (150 mL) was added aq. NaOH (2 g, 0.05 mol, in 50 mL H₂O) indropwise at room temperature. The slurry was continued to stir for 20min, filtered and washed with water (10 mL) and ethyl ether (50 mL).Then the filter cake was dried under reduced pressure at 50° C. to give62 g (83%) of the desired compound. LC/MS (M−1): 531; H-NMR (300 MHz,CD₃OD) δ: 7.21-6.98 (m, 10H), 5.40-5.36 (t, 1H, J=6.9 Hz), 4.38-4.34 (t,1H, J=7.5 Hz), 3.61 (s, 3H), 3.24-3.23 (m, 1H), 3.11-3.01 (m, 2H),2.81-2.74 (m, 3H), 1.31-1.26 (t, 3H, J=7.5 Hz); HPLC: 98.5%.

Methods

Disclosed are methods for the treatment of diseases or conditions of theeye, especially diabetic macular edema, age-related macular degeneration(wet form), choroidal neovascularization, diabetic retinopathy, ocularischemia, uveitis, retinal vein occlusion (central or branch), oculartrauma, surgery induced edema, surgery induced neovascularization,cystoid macular edema, ocular ischemia, uveitis, and the like. Thesediseases or conditions are characterized by changes in the ocularvasculature whether progressive or non-progressive, whether a result ofan acute disease or condition, or a chronic disease or condition. Thesediseases can be characterized by an increased level of plasma VascularEndothelial Growth Factor.

In some embodiments, the disclosed methods relate to the administrationof the HPTP-β inhibitor or a pharmaceutically acceptable salt thereof,as well as compositions comprising the HPTP-β inhibitor or apharmaceutically acceptable salt thereof.

In some embodiments, the methods of the disclosure are drawn towardsco-administration of a HPTP-β inhibitor or a pharmaceutically acceptablesalt thereof which stabilizes the vasculature against leakage and one ormore anti-VEGF agents.

In some embodiments, the methods of the disclosure are drawn towardsco-administration of a HPTP-β inhibitor or a pharmaceutically acceptablesalt thereof which stabilizes the vasculature against neovascularizationand one or more anti-VEGF agents.

In some embodiments, the inhibitor stabilizes the vasculature againstleakage and neovascularization.

In one embodiment of the disclosed methods, a human subject with atleast one visually impaired eye is treated with from about 0.1 mg toabout 100 mg of the HPTP-β inhibitor or a pharmaceutically acceptablesalt thereof via subcutaneous or intravitreal injection. Improvement ofclinical symptoms can be monitored by one or more methods known to theart, for example, indirect ophthalmoscopy, fundus photography,fluorescein angiopathy, electroretinography, external eye examination,slit lamp biomicroscopy, applanation tonometry, pachymetry, opticalcoherence tomography and autorefaction. As described herein, the dosingcan occur at any frequency determined by the administrator. Aftercessation of the anti-VEGF agent treatment, subsequent doses can beadministered weekly or monthly, e.g., with a frequency of 2-8 weeks or1-12 months apart depending upon the response.

One aspect of the disclosed methods relates to diseases that are adirect or indirect result of diabetes, inter alia, diabetic macularedema and diabetic retinopathy. The ocular vasculature of the diabeticbecomes unstable over time leading to conditions such asnon-proliferative retinopathy, macular edema, and proliferativeretinopathy. As fluid leaks into the center of the macula, the part ofthe eye where sharp, straight-ahead vision occurs, the buildup of fluidand the associated protein begin to deposit on or under the macula. Thisresults in swelling that causes the subject's central vision togradually become distorted. This condition is referred to as “macularedema.” Another condition that may occur is non-proliferativeretinopathy in which vascular changes, such as microaneurysms, outsidethe macular region of the eye may be observed.

These conditions may or may not progress to diabetic proliferativeretinopathy which is characterized by increased neovascularization.These new blood vessels are fragile and are susceptible to bleeding. Theresult is scaring of the retina, as well as occlusion or total blockageof the light pathway through the eye due to the over formation of newblood vessels. Typically subjects having diabetic macular edema aresuffering from the non-proliferative stage of diabetic retinopathy;however, it is not uncommon for subjects to only begin manifestingmacular edema at the onset of the proliferative stage.

Diabetic retinopathy is the most common cause of vision loss inworking-aged Americans (Klein R et al., “The Wisconsin EpidemiologicStudy of Diabetic Retinopathy. II. Prevalence and risk of diabeticretinopathy when age at diagnosis is less than 30 years,” Arch.Ophthalmol. 1984, 102:520-526). Severe vision loss occurs due totractional retinal detachments that complicate retinalneovascularization (NV), but the most common cause of moderate visionloss is diabetic macular edema (DME). The pathogenesis of diabeticmacular edema is not completely understood, but hypoxia is acontributing factor (Nguyen QD et al., “Supplemental inspired oxygenimproves diabetic macular edema; a pilot study,” Invest. Ophthalmol.Vis. Sci. 2003, 45:617-624). Vascular endothelial growth factor (Vegf)is a hypoxia-regulated gene and VEGF levels are increased in hypoxic orischemic retina. Injection of VEGF into mouse eyes causes breakdown ofthe inner blood-retinal barrier

(See, Derevjanik NL et al. Quantitative assessment of the integrity ofthe blood-retinal barrier in mice, Invest. Ophthalmol. Vis. Sci. 2002,43:2462-2467) and sustained release of VEGF in the eyes of monkeyscauses macular edema (Ozaki H et a/.,“Intravitreal sustained release ofVEGF causes retinal neovascularization in rabbits and breakdown of theblood-retinal barrier in rabbits and primates,” Exp Eye Res 1997,64:505-517). This combination of observations in patients and animalmodels led to the hypothesis that VEGF plays an important role in thepathogenesis of diabetic macular edema. This hypothesis has beenconfirmed by several clinical trials that have shown that VEGFantagonists reduce foveal thickening and improve vision in patients withdiabetic macular edema (Nguyen QD et al., “Vascular endothelial growthfactor is a critical stimulus for diabetic macular edema,” Am. J.Ophthalmol. 2006, 142:961-969; and Nguyen QD et al. “Primary End Point(Six Months) Results of the Ranibizumab for Edema of the mAcula inDiabetes (READ-2) Study,” Ophthalmology 2009, 116:2175-2181).

The effects of VEGF on vascular endothelial cells are modulated by Tie2receptors, which are selectively expressed on vascular endothelial cellsand are required for embryonic vascular development (Dumont D J et al.,“Dominant-negative and targeted null mutations in the endothelialreceptor tyrosine kinase, tek, reveal a critical role in vasculogenesisof the embryo,” Genes Dev. 1994, 8:1897-1909). Angiopoietin 1 (Ang1)binds Tie2 with high affinity and initiates phosphorylation anddownstream signaling (Davis S et al., “Isolation of angiopoietin-1, aligand for the TIE2 receptor, by secretion-trap expression cloning,”Cell 1996, 87:1161-1169). Mice deficient in Ang1 die around E12.5 withvascular defects similar to, but less severe than those seen inTie2-deficient mice. Angiopoietin 2 (Ang2) binds Tie2 with highaffinity, but does not stimulate phosphorylation in cultured endothelialcells. It acts as a competitive inhibitor of Ang1 and transgenic miceoverexpressing Ang2 have a phenotype similar to Ang1-deficient mice.Several lines of evidence indicate that Ang2 is a developmentally- andhypoxia-regulated permissive factor for VEGF-induced neovascularizationin the retina (Hackett S F et al., “Angiopoietin 2 expression in theretina: upregulation during physiologic and pathologicneovascularization,” J. Cell. Physiol. 2000, 184:275-284). Doubletransgenic Tet/opsin/ang2 and Tet/opsin/ang1 mice with inducibleexpression of Ang2 or Ang1, respectively, have also helped to elucidatethe role of Tie2 in the retina (Nambu H et al., “Angiopoietin 1 inhibitsocular neovascularization and breakdown of the blood-retinal barrier,”Gene Ther. 2004, 11:865-873). In mice with ischemic retinopathy,increased expression of Ang2 when VEGF is high (P12-17) increasesretinal neovascularization, but increased expression at P20 when VEGFlevels have come down, hastens regression of retinal neovascularizationand findings were similar in other models of ocular neovascularization.In contrast, increased expression of Ang1 suppressed neovascularizationand reduced vascular leakage in several models. Therefore, Ang2 reducesstabilizing signals from the matrix making endothelial cells dependentupon VEGF and other soluble stimulators; when VEGF is high,neovascularization is stimulated and when VEGF is low,neovascularization regresses. In contrast, Ang1 increases stabilizingsignals from the matrix and makes the vasculature unresponsive tosoluble stimulators like VEGF.

Angiopoietin 2 binds Tie2, but does not stimulate phosphorylation andtherefore acts as an antagonist under most circumstances. In the eye,angiopoietin 2 is upregulated at sites of neovascularization and acts asa permissive factor for VEGF. Increased expression of VEGF in the retinadoes not stimulate sprouting of neovascularization from the superficialor intermediate capillary beds of the retina or the choriocapillaris,but does stimulate sprouting from the deep capillary bed where there isconstitutive expression of angiopoietin 2 (Hackett SF et al.,“Angiopoietin-2 plays an important role in retinal angiogenesis,” J.Cell. Physiol. 2002, 192:182-187). Co-expression of VEGF andangiopoietin 2 at the surface of the retina causes sprouting ofneovascularization from the superficial retinal capillaries (Oshima Y etal., “Angiopoietin-2 enhances retinal vessel sensitivity to vascularendothelial growth factor,” J. Cell. Physiol. 2004, 199:412-417). Indouble transgenic mice with inducible expression of angiopoietin 2 inthe retina, expression of angiopoietin 2 when VEGF levels were highmarkedly enhanced neovascularization and expression of angiopoietin 2when VEGF levels were low caused regression of neovascularization. Indouble transgenic mice with inducible expression of angiopoietin 1, theinduced expression of angiopoietin 1 in the retina strongly suppressedVEGF-induced vascular leakage or neovascularization (Nambu H et al.,“Angiopoietin 1 inhibits ocular neovascularization and breakdown of theblood-retinal barrier,” Gene Ther. 2004, 11:865-873). In fact, in micewith high expression of VEGF in the retina which develop severe NV andretinal detachment, angiopoietin 1 is able to prevent the VEGF-induceddetachments.

Regulation of Tie2 also occurs through an endothelial-specificphosphatase, vascular endothelial protein tyrosine phophatase (VE-PTP)in mice (Fachinger G et al., “Functional interaction of vascularendothelial-protein-tyrosine phosphatase with the angiopoietin receptorTie-2,” Oncogene 1999, 18:5948-5943) and its human orthologue humanprotein tyrosine phosphatase-β (HPTP-β) (Krueger NX et al., “Structuraldiversity and evolution of human receptor-like protein tyrosinephosphatases,” EMBO J. 1990, 9:3241-3252). Mice deficient in VE-PTP dieat El° with severe defects in vascular remodeling and maturation ofdeveloping vasculature. Silencing of HPTP-β in cultured humanendothelial cells, enhances Ang1-induced phosphorylation of Tie2 andsurvival-promoting activity while hypoxia increases expression of HPTP-βand reduces Ang1-induced phosphorylation of Tie2 (Yacyshyn OK et al.,“Thyrosine phosphatase beta regulates angiopoietin-Tie2 signaling inhuman endothelial cells,” Angiogenesis 2009, 12:25-33).

Macular degeneration is a condition characterized by a gradual loss orimpairment of eyesight due to cell and tissue degeneration of the yellowmacular region in the center of the retina. Macular degeneration isoften characterized as one of two types, non-exudative (dry form) orexudative (wet form). Although both types are bilateral and progressive,each type may reflect different pathological processes. The wet form ofage-related macular degeneration (AMD) is the most common form ofchoroidal neovascularization and a leading cause of blindness in theelderly. AMD affects millions of Americans over the age of 60, and isthe leading cause of new blindness among the elderly.

Choroidal neovascular membrane (CNVM) is a problem that is related to awide variety of retinal diseases, but is most commonly linked toage-related macular degeneration. With CNVM, abnormal blood vesselsstemming from the choroid (the blood vessel-rich tissue layer justbeneath the retina) grow up through the retinal layers. These newvessels are very fragile and break easily, causing blood and fluid topool within the layers of the retina.

Diabetes (diabetes mellitus) is a metabolic disease caused by theinability of the pancreas to produce insulin or to use the insulin thatis produced. The most common types of diabetes are type 1 diabetes(often referred to as Juvenile Onset Diabetes Mellitus) and type 2diabetes (often referred to as Adult Onset Diabetes Mellitus). Type 1diabetes results from the body's failure to produce insulin due to lossof insulin producing cells, and presently requires the person to injectinsulin. Type 2 diabetes generally results from insulin resistance, acondition in which cells fail to use insulin properly.

Diabetes can be correlated to a large number of other conditions,including conditions or diseases of the eye including diabeticretinopathy (DR) and diabetic macular edema (DME) which are leadingcauses of vision loss and blindness in most developed countries. Theincreasing number of individuals with diabetes worldwide suggests thatDR and DME continues to be major contributors to vision loss andassociated functional impairment for years to come.

Diabetic retinopathy is a complication of diabetes that results fromdamage to the blood vessels of the light-sensitive tissue at the back ofthe eye (retina). At first, diabetic retinopathy may cause no symptomsor only mild vision problems. Eventually, however, diabetic retinopathycan result in blindness. Diabetic retinopathy can develop in anyone whohas type 1 diabetes or type 2 diabetes.

At its earliest stage, non-proliferative retinopathy, microaneurysmsoccur in the retina's tiny blood vessels. As the disease progresses,more of these blood vessels become damaged or blocked and these areas ofthe retina send signals into the regional tissue to grow new bloodvessels for nourishment. This stage is called proliferative retinopathy.The new blood vessels grow along the retina and along the surface of theclear, vitreous gel that fills the inside of the eye. By themselves,these blood vessels do not cause symptoms or vision loss. However, theyhave thin, fragile walls and without timely treatment, these new bloodvessels can leak blood (whole blood or some constituents thereof) whichcan result in severe vision loss and even blindness. Also, fluid canleak into the center of the macula, the part of the eye where sharp,straight-ahead vision occurs. The fluid and the associated protein beginto deposit on or under the macula swell the patient's central visionbecomes distorted. This condition is called macular edema. It can occurat any stage of diabetic retinopathy, although it is more likely tooccur as the disease progresses. About half of the people withproliferative retinopathy also have macular edema.

Uveitis is a condition in which the uvea becomes inflamed. The eye isshaped much like a tennis ball, hollow on the inside with threedifferent layers of tissue surrounding a central cavity. The outermostis the sclera (white coat of the eye) and the innermost is the retina.The middle layer between the sclera and the retina is called the uvea.The uvea contains many of the blood vessels that nourish the eye.Complications of uveitis include glaucoma, cataracts or new blood vesselformation (neovascularization).

Ocular trauma is any sort of physical or chemical injury to the eye.Ocular trauma can affect anyone and major symptoms include redness orpain in the affected eye. Neither symptom may occur if tiny projectilesare the cause of the trauma.

Surgery-induced edema is the development of swelling in the eye tissuesfollowing surgery on the retina or other part of the eye. Cystoidmacular edema (CME) is an example of this phenomenon. CME can occur notonly in people who have had cataract surgery, but also those withdiabetes, retinitis pigmentosa, AMD, or conditions that cause chronicinflammation in the eye. The major symptoms of CME are blurred ordecreased central vision.

Ocular ischemic syndrome (OIS) encompasses the signs and symptoms thatresult from chronic vascular insufficiency. It is caused by ocularhypoperfusion due to occlusion or stenosis of the common or internalcarotid arteries. OIS generally affects those between the ages of 50-80and they may also have systemic diseases such as hyl)ertension ordiabetes. The major symptoms of OIS are orbital pain, vision loss,changes of the visual field, asymmetric cataract, and sluggish reactionto light, among a variety of other symptoms.

Retinal vein occlusion (RVO) is the most common retinal vascular diseaseafter diabetic retinopathy. Depending on the area of retinal venousdrainage effectively occluded, it is broadly classified as eithercentral retinal vein occlusion (CRVO), hemispheric retinal veinocclusion (HRVO), or branch retinal vein occlusion (BRVO). It has beenobserved that each of these has two subtypes. Presentation of RVO ingeneral is with variable painless visual loss with any combination offundal findings consisting of retinal vascular tortuosity, retinalhemorrhages (blot and flame shaped), cotton wool spots, optic discswelling and macular edema. In a CRVO, retinal hemorrhages can be foundin all four quadrants of the fundus, whilst these are restricted toeither the superior or inferior fundal hemisphere in a HRVO. In a BRVO,hemorrhages are largely localized to the area drained by the occludedbranch retinal vein. Vision loss occurs secondary to macular edema orischemia.

Angiogenesis, the process of creating new blood vessels frompre-existing vessels, is essential to a wide range of physiological andpathological events including embryological development, menstruation,wound healing, and tumor growth. Most, if not all, tumors requireangiogenesis to grow and proliferate. VEGF has been shown to a majorfactor in angiogenesis where it can increase vessel permeability andcapillary number. Due to the essential function of angiogenesis in tumordevelopment, much effort has been put forth to develop therapies thattarget regulators of angiogenesis, including VEGF.

Vascular endothelial growth factor (VEGF) is a protein that is primarilyfound in endothelial cells and has functions in vasculogenesis,angiogenesis, and permeabilization of blood vessels. The expression ofVEGF is induced by hypoxia, activated oncogenes, and cytokines. It hasbeen found that VEGF activation not only leads to angiogenesis in normalhuman cells and tissues, but also angiogenesis in tumors, allowing fortumor progression and growth. Inhibition of VEGF inhibits tumor growthleading to tumor regression. A variety of retinopathies are associatedwith increased levels of VEGF; ischemia in the eye leads to an inductionof VEGF production due to lack of oxygen. This increase in VEGF cancause hyperproliferation of blood vessels in the retina, eventuallyleading to blindness. The disclosed HPTP-β inhibitors act to stabilizeocular vasculature and, in some embodiments, a compound of the inventionserves to counter act the stimulation caused by VEGF and otherinflammatory agents that can be present in the diseased retina. In someembodiments, administration of HPTP-β inhibitors to a subject can beused to maintain the level of disease reversal after administration ofanti-VEGF drugs to the subject have been withdrawn.

Diabetic retinopathy, if left untreated, can lead ultimately toblindness. Indeed, diabetic retinopathy is the leading cause ofblindness in working-age populations.

Therefore, the disclosed methods relate to preventing, treating,controlling, abating, and/or otherwise minimizing ocularneovascularization in a subject having diabetes or a subject diagnosedwith diabetes. In addition, subjects having or subjects diagnosed withdiabetes can be alerted to or can be made aware of the risks ofdeveloping diabetes-related blindness, therefore the present methods canbe used to prevent or delay the onset of non-proliferative retinopathyin subjects known to be at risk. Likewise, the present methods can beused for treating subjects having or being diagnosed withnon-proliferative diabetic retinopathy to prevent progression of thecondition.

The disclosed methods relate to preventing or controlling ocularneovascularization or treating a disease or condition that is related tothe onset of ocular neovascularization by administering to a subject the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid s and one or more anti-VEGF agents as disclosed herein.

Unlike previous ocular treatments which comprise administration of ananti-VEGF agent, inter alia, ranibizumab (Lucentis™), bevacizumab(Avastin™) and aflibercept (Eylea™), wherein these vascular leakinhibitors are injected directly into the eye itself, the HPTP-βinhibitor or a pharmaceutically acceptable salt thereof can beadministered systemically or into the eye. The HPTP-β inhibitor or apharmaceutically acceptable salt thereof can be used to increase orenhance the effect of anti-VEGF agents, thereby improving the rate andmagnitude of the response and reducing the number of treatments.

In one aspect, the HPTP-β inhibitor or a pharmaceutically acceptablesalt thereof are administered in combination with one or morepharmaceutical compounds or compositions useful for treating oculardiseases. In one embodiment, the present disclosure relates to a methodfor treating an ocular disease, comprising administering:

-   -   a) a HPTP-β inhibitor or a pharmaceutically acceptable salt        thereof; and    -   b) ranibizumab.

In one aspect of the disclosure the methods comprise administering:

-   -   a) a HPTP-β inhibitor or a pharmaceutically acceptable salt        thereof as disclosed herein; and    -   b) ranibizumab.

In another aspect the methods comprise administering:

-   -   a) a HPTP-β inhibitor having the formula:

-   -   -   wherein R² and R⁴ are chosen from:        -   i) hydrogen;        -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆            branched, or C₃-C₆ cyclic alkyl;        -   iii) substituted or unsubstituted phenyl; or        -   iv) substituted or unsubstituted thiophenyl;        -   R¹ is C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl;        -   R^(5a) is chosen from:        -   i) hydrogen;        -   ii) C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; or        -   iii) benzyl; or        -   a pharmaceutically acceptable salt thereof; and

    -   b) ranibizumab.

A non-limiting embodiment of this aspect relates to methods comprisingadministering:

-   -   a) a HPTP-β inhibitor having the formula:

-   -   -   wherein R² and R⁴ are chosen from:        -   i) hydrogen;        -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆            branched, or C₃-C₆ cyclic alkyl;        -   iii) substituted or unsubstituted phenyl; or        -   iv) substituted or unsubstituted thiophenyl;        -   R¹ is C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl;            or        -   a pharmaceutically acceptable salt; and

    -   b) ranibizumab.

The compounds can be administered in any order convenient to the user orto the subject receiving treatment. In one non-limiting example of thedisclosed methods, a compound herein or a pharmaceutically acceptablesalt thereof is administered first followed by administration ofranibizumab. In another iteration of this embodiment ranibizumab isadministered first followed by administration of the compound herein ora pharmaceutically acceptable salt thereof. The time period betweendosing/administration of the first component of treatment can be anytime period convenient to the formulator or subject receiving treatment.For example, the compound herein or a pharmaceutically acceptable saltthereof can be administered minutes, hours, days or weeks prior to theadministration of ranibizumab or more than one dosage of the compoundherein or a pharmaceutically acceptable salt thereof can be given toestablish a therapeutic amount in the subject being treated.

In another iteration, a compound herein or a pharmaceutically acceptablesalt thereof and ranibizumab can be given in alternatingadministrations. For example, the compound herein or a pharmaceuticallyacceptable salt thereof can be administered then after a time desired bythe administrator ranibizumab is administered.

In a further iteration, the compound herein or a pharmaceuticallyacceptable salt thereof are administered daily in one or more doses andthe ramibizumab is administered according to a separate schedule. Forexample, in addition to daily dosing of the compound herein, ranibizumabcan be administered once a month, once every 2 months, once every 3months, once every 4 months, once every 6 months, etc.

In another non-limiting example of the disclosed methods, a compoundherein or a pharmaceutically acceptable salt thereof is administeredfirst followed by administration of ranibizumab. In another iteration ofthis embodiment, ranibizumab is administered first followed byadministration of the compound herein or a pharmaceutically acceptablesalt thereof. The time period between dosing/administration of the firstcomponent of treatment can be any time period convenient to theformulator or subject receiving treatment. For example, the compoundherein or a pharmaceutically acceptable salt thereof can be administeredminutes, hours, days or weeks prior to the administration of ranibizumabor more than one dosage of the compound herein or a pharmaceuticallyacceptable salt thereof can be given to establish a therapeutic amountin the subject being treated.

In another iteration, the compound herein or a pharmaceuticallyacceptable salt thereof and ranibizumab can be given in alternatingadministrations. For example, the compound herein or a pharmaceuticallyacceptable salt thereof can be administered then after a time desired bythe administrator ranibizumab is administered.

In a further iteration, the compound herein or a pharmaceuticallyacceptable salt thereof are administered daily in one or more doses andthe ramibizumab is administered according to a separate schedule. Forexample, in addition to daily dosing of the compound herein, ranibizumabcan be administered once a month, once every 2 months, once every 3months, once every 4 months, once every 6 months, etc.

In a further non-limiting example of the disclosed methods, a compoundherein or a pharmaceutically acceptable salt thereof is administeredfirst followed by administration of ranibizumab. In another iteration ofthis embodiment ranibizumab is administered first followed byadministration of the compound herein or a pharmaceutically acceptablesalt thereof. The time period between dosing/administration of the firstcomponent of treatment can be any time period convenient to theformulator or subject receiving treatment. For example, the compoundherein or a pharmaceutically acceptable salt thereof can be administeredminutes, hours, days or weeks prior to the administration of ranibizumabor more than one dosage of the compound herein or a pharmaceuticallyacceptable salt thereof can be given to establish a therapeutic amountin the subject being treated.

In another iteration, the compound herein or a pharmaceuticallyacceptable salt thereof and ranibizumab can be given in alternatingadministrations. For example, the compound herein or a pharmaceuticallyacceptable salt thereof can be administered then after a time desired bythe administrator ranibizumab is administered.

In a further iteration, the compound herein or a pharmaceuticallyacceptable salt thereof are administered daily in one or more doses andthe ramibizumab is administered according to a separate schedule. Forexample, in addition to daily dosing of the compound herein, ranibizumabcan be administered once a month, once every 2 months, once every 3months, once every 4 months, once every 6 months, etc.

The dosage for ranibizumab can be in any amount necessary. In oneembodiment, ranibizumab is administered in an amount from about 0.05 mgto about 1.5 mg. In a further embodiment, ranibizumab is administered inan amount from about 0.1 mg to about 1.5 mg. In another embodiment,ranibizumab is administered in an amount from about 0.05 mg to about 1mg. In a still further embodiment, ranibizumab is administered in anamount from about 0.1 mg to about 1 mg. In one non-limiting example,ranibizumab is administered in an amount of approximately 0.5 mg. Theamount of an antibody, such as ranibizumab, administered per treatmentcan be in any amount, for example, about 0.05 mg, about 0.06 mg, about0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.11 mg,about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16mg, about 0.17, mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about0.21 mg, about 0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg,about 0.26 mg, about 0.27, mg, about 0.28 mg, about 0.29 mg, about 0.3mg, about 0.31 mg, about 0.32 mg, about 0.33 mg, about 0.34 mg, about0.35 mg, about 0.36 mg, about 0.37, mg, about 0.38 mg, about 0.39 mg,about 0.4 mg, about 0.41 mg, about 0.42 mg, about 0.43 mg, about 0.44mg, about 0.45 mg, about 0.46 mg, about 0.47, mg, about 0.48 mg, about0.49 mg, about 0.5 mg, about 0.51 mg, about 0.52 mg, about 0.53 mg,about 0.54 mg, about 0.55 mg, about 0.56 mg, about 0.57, mg, about 0.58mg, about 0.59 mg, about 0.6 mg, about 0.61 mg, about 0.62 mg, about0.63 mg, about 0.64 mg, about 0.65 mg, about 0.66 mg, about 0.67, mg,about 0.68 mg, about 0.69 mg, about 0.7 mg, about 0.71 mg, about 0.72mg, about 0.73 mg, about 0.74 mg, about 0.75 mg, about 0.76 mg, about0.77, mg, about 0.78 mg, about 0.79 mg, about 0.8 mg, about 0.81 mg,about 0.82 mg, about 0.83 mg, about 0.84 mg, about 0.85 mg, about 0.86mg, about 0.87, mg, about 0.88 mg, about 0.89 mg, about 0.9 mg, about0.91 mg, about 0.92 mg, about 0.93 mg, about 0.94 mg, about 0.95 mg,about 0.96 mg, about 0.97, mg, about 0.98 mg, about 0.99 mg, about 1 mg,about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg,about 9 mg, or about 10 mg.

If the antibody is not administered simulatanously with the othercompound herein, then the time between administration of the compoundand the antibody can range, for example, from about 1 minute, about 2minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 2hours, about 3 hours, about 4 hours, about 5 hours, about 10 hours,about 20 hours, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks,to about 4 weeks.

In another embodiment, the present disclosure relates to a method fortreating an ocular disease, comprising administering:

-   -   a) a HPTP-β inhibitor or a pharmaceutically acceptable salt        thereof; and    -   b) bevacizumab.

In one aspect of the disclosure the methods comprise administering:

-   -   a) a HPTP-β inhibitor or a pharmaceutically acceptable salt        thereof as disclosed herein; and    -   b) bevacizumab.

In another aspect the methods comprise administering:

-   -   a) a HPTP-β inhibitor having the formula:

-   -   -   wherein R² and R⁴ are chosen from:        -   i) hydrogen;        -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆            branched, or C₃-C₆ cyclic alkyl;        -   iii) substituted or unsubstituted phenyl; or        -   iv) substituted or unsubstituted thiophenyl;        -   R¹ is C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl;        -   R^(5a) is chosen from:        -   i) hydrogen;        -   ii) C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; or        -   iii) benzyl; or        -   a pharmaceutically acceptable salt thereof; and

    -   b) bevacizumab.

A non-limiting embodiment of this aspect relates to methods comprisingadministering:

-   -   a) a HPTP-β inhibitor having the formula:

-   -   -   wherein R² and R⁴ are chosen from:        -   i) hydrogen;        -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆            branched, or C₃-C₆ cyclic alkyl;        -   iii) substituted or unsubstituted phenyl; or        -   iv) substituted or unsubstituted thiophenyl;        -   R¹ is C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl;            or        -   a pharmaceutically acceptable salt; and

    -   b) bevacizumab.

The compounds can be administered in any order convenient to the user orto the subject receiving treatment. In one non-limiting example of thedisclosed methods4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof is administered firstfollowed by administration of bevacizumab. In another iteration of thisembodiment bevacizumab is administered first followed by administrationof the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. The time periodbetween dosing/administration of the first component of treatment can beany time period convenient to the formulator or subject receivingtreatment. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredminutes, hours, days or weeks prior to the administration of bevacizumabor more than one dosage of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be given toestablish a therapeutic amount in the subject being treated.

In another iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof and bevacizumab canbe given in alternating administrations. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredthen after a time desired by the administrator bevacizumab isadministered.

In a further iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof are administereddaily in one or more doses and the ramibizumab is administered accordingto a separate schedule. For example, in addition to daily dosing of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid s, bevacizumab can be administered once a month, once every 2months, once every 3 months, once every 4 months, once every 6 months,etc.

In another non-limiting example of the disclosed methods4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof is administered firstfollowed by administration of bevacizumab. In another iteration of thisembodiment bevacizumab is administered first followed by administrationof the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. The time periodbetween dosing/administration of the first component of treatment can beany time period convenient to the formulator or subject receivingtreatment. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredminutes, hours, days or weeks prior to the administration of bevacizumabor more than one dosage of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be given toestablish a therapeutic amount in the subject being treated.

In another iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof and bevacizumab canbe given in alternating administrations. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredthen after a time desired by the administrator bevacizumab isadministered.

In a further iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof are administereddaily in one or more doses and the ramibizumab is administered accordingto a separate schedule. For example, in addition to daily dosing of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid s, bevacizumab can be administered once a month, once every 2months, once every 3 months, once every 4 months, once every 6 months,etc.

In a further non-limiting example of the disclosed methods4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof is administered firstfollowed by administration of bevacizumab. In another iteration of thisembodiment bevacizumab is administered first followed by administrationof the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. The time periodbetween dosing/administration of the first component of treatment can beany time period convenient to the formulator or subject receivingtreatment. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredminutes, hours, days or weeks prior to the administration of bevacizumabor more than one dosage of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be given toestablish a therapeutic amount in the subject being treated.

In another iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof and bevacizumab canbe given in alternating administrations. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredthen after a time desired by the administrator bevacizumab isadministered.

In a further iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof are administereddaily in one or more doses and the ramibizumab is administered accordingto a separate schedule. For example, in addition to daily dosing of4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof, bevacizumab can beadministered once a month, once every 2 months, once every 3 months,once every 4 months, once every 6 months, etc.

The dosage for bevacizumab can be in any amount necessary. In oneembodiment, bevacizumab is administered in an amount from about 0.1 mgto about 5 mg. In a further embodiment, bevacizumab is administered inan amount from about 0.1 mg to about 3 mg. In another embodiment,bevacizumab is administered in an amount from about 0.5 mg to about 3mg. In a still further embodiment, bevacizumab is administered in anamount from about 0.5 mg to about 2 mg. In one non-limiting example,bevacizumab is administered in an amount of 1.2 mg. The amount ofbevacizumab administered per treatment can be in any amount, forexample, about 0.5 mg, about 0.51 mg, about 0.52 mg, about 0.53 mg,about 0.54 mg, about 0.55 mg, about 0.56 mg, about 0.57, mg, about 0.58mg, about 0.59 mg, about 0.6 mg, about 0.61 mg, about 0.62 mg, about0.63 mg, about 0.64 mg, about 0.65 mg, about 0.66 mg, about 0.67, mg,about 0.68 mg, about 0.69 mg, about 0.7 mg, about 0.71 mg, about 0.72mg, about 0.73 mg, about 0.74 mg, about 0.75 mg, about 0.76 mg, about0.77, mg, about 0.78 mg, about 0.79 mg, about 0.8 mg, about 0.81 mg,about 0.82 mg, about 0.83 mg, about 0.84 mg, about 0.85 mg, about 0.86mg, about 0.87, mg, about 0.88 mg, about 0.89 mg, about 0.9 mg, about0.91 mg, about 0.92 mg, about 0.93 mg, about 0.94 mg, about 0.95 mg,about 0.96 mg, about 0.97, mg, about 0.98 mg, about 0.99 mg, about 1 mg,about 1.01 mg, about 1.02 mg, about 1.03 mg, about 1.04 mg, about 1.05mg, about 1.06 mg, about 1.07, mg, about 1.08 mg, about 1.09 mg, 1.1 mg,about 1.11 mg, about 1.12 mg, about 1.13 mg, about 1.14 mg, about 1.15mg, about 1.16 mg, about 1.17, mg, about 1.18 mg, about 1.19 mg, about1.2 mg, about 1.21 mg, about 1.22 mg, about 1.23 mg, about 1.24 mg,about 1.25 mg, about 1.26 mg, about 1.27, mg, about 1.28 mg, about 1.29mg, about 1.3 mg, about 1.31 mg, about 1.32 mg, about 1.33 mg, about1.34 mg, about 1.35 mg, about 1.36 mg, about 1.37, mg, about 1.38 mg,about 1.39 mg, about 1.4 mg, about 1.41 mg, about 1.42 mg, about 1.43mg, about 1.44 mg, about 1.45 mg, about 1.46 mg, about 1.47, mg, about1.48 mg, about 1.49 mg, about 1.5 mg, about 1.51 mg, about 1.52 mg,about 1.53 mg, about 1.54 mg, about 1.55 mg, about 1.56 mg, about 1.57,mg, about 1.58 mg, about 1.59 mg, or about 1.6 mg.

In another embodiment, the present disclosure relates to a method fortreating an ocular disease, comprising administering:

-   -   a) a HPTP-β inhibitor or a pharmaceutically acceptable salt        thereof; and    -   b) aflibercept.

In one aspect of the disclosure the methods comprise administering:

-   -   a) a HPTP-β inhibitor or a pharmaceutically acceptable salt        thereof as disclosed herein; and    -   b) aflibercept.

In another aspect the methods comprise administering:

-   -   a) a HPTP-β inhibitor having the formula:

-   -   -   wherein R² and R⁴ are chosen from:        -   i) hydrogen;        -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆            branched, or C₃-C₆ cyclic alkyl;        -   iii) substituted or unsubstituted phenyl; or        -   iv) substituted or unsubstituted thiophenyl;        -   R¹ is C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl;        -   R^(5a) is chosen from:        -   i) hydrogen;        -   ii) C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl; or        -   iii) benzyl; or        -   a pharmaceutically acceptable salt thereof; and

    -   b) aflibercept.

A non-limiting embodiment of this aspect relates to methods comprisingadministering:

-   -   a) a HPTP-β inhibitor having the formula:

-   -   -   wherein R² and R⁴ are chosen from:        -   i) hydrogen;        -   ii) substituted or unsubstituted C₁-C₆ linear, C₃-C₆            branched, or C₃-C₆ cyclic alkyl;        -   iii) substituted or unsubstituted phenyl; or        -   iv) substituted or unsubstituted thiophenyl;        -   R¹ is C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic alkyl;            or        -   a pharmaceutically acceptable salt; and

    -   b) aflibercept.

The compounds can be administered in any order convenient to the user orto the subject receiving treatment. In one non-limiting example of thedisclosed methods4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof is administered firstfollowed by administration of aflibercept. In another iteration of thisembodiment aflibercept is administered first followed by administrationof the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. The time periodbetween dosing/administration of the first component of treatment can beany time period convenient to the formulator or subject receivingtreatment. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredminutes, hours, days or weeks prior to the administration of afliberceptor more than one dosage of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be given toestablish a therapeutic amount in the subject being treated.

In another iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof and aflibercept canbe given in alternating administrations. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredthen after a time desired by the administrator aflibercept isadministered.

In a further iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof are administereddaily in one or more doses and the ramibizumab is administered accordingto a separate schedule. For example, in addition to daily dosing of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid s, aflibercept can be administered once a month, once every 2months, once every 3 months, once every 4 months, once every 6 months,etc.

In another non-limiting example of the disclosed methods4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof is administered firstfollowed by administration of aflibercept. In another iteration of thisembodiment aflibercept is administered first followed by administrationof the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. The time periodbetween dosing/administration of the first component of treatment can beany time period convenient to the formulator or subject receivingtreatment. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredminutes, hours, days or weeks prior to the administration of afliberceptor more than one dosage of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be given toestablish a therapeutic amount in the subject being treated.

In another iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof and aflibercept canbe given in alternating administrations. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredthen after a time desired by the administrator aflibercept isadministered.

In a further iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof are administereddaily in one or more doses and the ramibizumab is administered accordingto a separate schedule. For example, in addition to daily dosing of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid s, aflibercept can be administered once a month, once every 2months, once every 3 months, once every 4 months, once every 6 months,etc.

In a further non-limiting example of the disclosed methods4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof is administered firstfollowed by administration of aflibercept. In another iteration of thisembodiment aflibercept is administered first followed by administrationof the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof. The time periodbetween dosing/administration of the first component of treatment can beany time period convenient to the formulator or subject receivingtreatment. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredminutes, hours, days or weeks prior to the administration of afliberceptor more than one dosage of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be given toestablish a therapeutic amount in the subject being treated.

In another iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof and aflibercept canbe given in alternating administrations. For example, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamideo]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof can be administeredthen after a time desired by the administrator aflibercept isadministered.

In a further iteration, the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid or a pharmaceutically acceptable salt thereof are administereddaily in one or more doses and the ramibizumab is administered accordingto a separate schedule. For example, in addition to daily dosing of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid s, aflibercept can be administered once a month, once every 2months, once every 3 months, once every 4 months, once every 6 months,etc.

The dosage for aflibercept can be in any amount necessary. In oneembodiment, aflibercept is administered in an amount from about 0.05 mgto about 5 mg. In a further embodiment, aflibercept is administered inan amount from about 0.1 mg to about 3 mg. In another embodiment,aflibercept is administered in an amount from about 0.5 mg to about 2.5mg. In a still further embodiment, aflibercept is administered in anamount from about 0.5 mg to about 2 mg. The amount of afliberceptadministered per treatment can be in any amount, for example, about 0.5mg, about 0.51 mg, about 0.52 mg, about 0.53 mg, about 0.54 mg, about0.55 mg, about 0.56 mg, about 0.57, mg, about 0.58 mg, about 0.59 mg,about 0.6 mg, about 0.61 mg, about 0.62 mg, about 0.63 mg, about 0.64mg, about 0.65 mg, about 0.66 mg, about 0.67, mg, about 0.68 mg, about0.69 mg, about 0.7 mg, about 0.71 mg, about 0.72 mg, about 0.73 mg,about 0.74 mg, about 0.75 mg, about 0.76 mg, about 0.77, mg, about 0.78mg, about 0.79 mg, about 0.8 mg, about 0.81 mg, about 0.82 mg, about0.83 mg, about 0.84 mg, about 0.85 mg, about 0.86 mg, about 0.87, mg,about 0.88 mg, about 0.89 mg, about 0.9 mg, about 0.91 mg, about 0.92mg, about 0.93 mg, about 0.94 mg, about 0.95 mg, about 0.96 mg, about0.97, mg, about 0.98 mg, about 0.99 mg, about 1 mg, about 1.01 mg, about1.02 mg, about 1.03 mg, about 1.04 mg, about 1.05 mg, about 1.06 mg,about 1.07, mg, about 1.08 mg, about 1.09 mg, 1.1 mg, about 1.11 mg,about 1.12 mg, about 1.13 mg, about 1.14 mg, about 1.15 mg, about 1.16mg, about 1.17, mg, about 1.18 mg, about 1.19 mg, about 1.2 mg, about1.21 mg, about 1.22 mg, about 1.23 mg, about 1.24 mg, about 1.25 mg,about 1.26 mg, about 1.27, mg, about 1.28 mg, about 1.29 mg, about 1.3mg, about 1.31 mg, about 1.32 mg, about 1.33 mg, about 1.34 mg, about1.35 mg, about 1.36 mg, about 1.37, mg, about 1.38 mg, about 1.39 mg,about 1.4 mg, about 1.41 mg, about 1.42 mg, about 1.43 mg, about 1.44mg, about 1.45 mg, about 1.46 mg, about 1.47, mg, about 1.48 mg, about1.49 mg, about 1.5 mg, about 1.51 mg, about 1.52 mg, about 1.53 mg,about 1.54 mg, about 1.55 mg, about 1.56 mg, about 1.57, mg, about 1.58mg, about 1.59 mg, about 1.6 mg, about 1.61 mg, about 1.62 mg, about1.63 mg, about 1.64 mg, about 1.65 mg, about 1.66 mg, about 1.67, mg,about 1.68 mg, about 1.69 mg, about 1.7 mg, about 1.71 mg, about 1.72mg, about 1.73 mg, about 1.74 mg, about 1.75 mg, about 1.76 mg, about1.77, mg, about 1.78 mg, about 1.79 mg, about 1.8 mg, about 1.81 mg,about 1.82 mg, about 1.83 mg, about 1.84 mg, about 1.85 mg, about 1.86mg, about 1.87, mg, about 1.88 mg, about 1.89 mg, about 1.9 mg, about1.91 mg, about 1.92 mg, about 1.93 mg, about 1.94 mg, about 1.95 mg,about 1.96 mg, about 1.97, mg, about 1.98 mg, about 1.99 mg, or about 2mg.

The HPTP-β inhibitors or a pharmaceutically acceptable salt thereof canbe administered in any amount necessary or convenient. For example, thecompound can be administered in an amount from about 0.1 mg to about 100mg per dose as described herein above in the disclosure relating to thecompositions.

The HPTP-β inhibitors or a pharmaceutically acceptable salt thereof canbe administered at any interval desired. For example, the compound canbe administered once a week, 2 times a week, 3 times a week, 4 times aweek, 6 times a week, 6 times a week, 7 times a week, 8 times a week, 9times a week or 10 times a week. The interval between daily dosing canbe any hourly interval, for example, every hour, every 2 hours, every 3hours, every 4 hours, every 5 hours, every 6 hours, every 7 hours, every8 hours, every 9 hours, every 10 hours, every 11 hours, and every 12hours. The administration of the compound can have irregular dosingschedules to accommodate either the person administering the compound orthe subject receiving the compound. As such, the compound can beadministered once a day, twice a day, three times a day, and the like.

In addition, the amount administered can be of the same amount in eachdose or the dosage can vary. For example, a first amount dosed in themorning and a second amount administered in the evening. The dosage foradministration can be varied depending upon the schedule of theanti-VEGF administration.

The HPTP-β inhibitors or a pharmaceutically acceptable salt thereof canbe administered in combination with any anti-VEGF agent in anycombination, for example, at the beginning of the treatment, at any timeduring the treatment or at any time after treatment with the anti-VEGFagent has concluded. In addition, the dosage of the HPTP-β inhibitors ora pharmaceutically acceptable salt thereof can be adjusted duringtreatment. Also, the amount of anti-VEGF agent can be adjusted duringtreatment.

Further non-limiting examples of anti-VEGF agents includesdexamethasone, fluocinolone and triamcinolone. In addition, thedisclosed methods can include implants which deliver an anti-VEGF agent.For example, HPTP-β inhibitors or a pharmaceutically acceptable saltthereof can be co-administered either before, during or after an implantis provided to a subject suffering from a disease or condition describedherein. For example, Ozurdex™ is an intraviteal implant which provides asupply of dexamethasone to a subject, Retisert™ and Iluvien™ areintraviteal implants which provides a supply of fluocinolone.

In one aspect, anti-VEGF treatments if typically given monthly, can havethe frequency of treatment extended, for example, to once every 3months, once every 6 months or yearly wherein the HPTP-β inhibitor or apharmaceutically acceptable salt thereof is administered at anyfrequency between treatments.

Also disclosed herein are methods for decreasing the Central FovealThickness (CFT) in a patient having a disease or condition as disclosedherein. The method comprises administering to an eye:

-   -   a) a HPTP-β inhibitor or a pharmaceutically acceptable salt        thereof; and    -   b) one or more anti-VEGF agents;        wherein the administration of the HPTP-β inhibitor or a        pharmaceutically acceptable salt thereof and the anti-VEGF agent        can be conducted in any manner desired by the administrator, for        example, as further described herein.

A further aspect relates to a method comprising administering to theeye:

-   -   a) a disclosed HPTP-β inhibitor or a pharmaceutically acceptable        salt thereof; and    -   b) one or more anti-VEGF agents;        wherein the administration of the HPTP-β inhibitor or a        pharmaceutically acceptable salt thereof and the anti-VEGF agent        can be conducted in any manner desired by the administrator, for        example, as further described herein.

In one aspect the decrease in Central Foveal Thickness is from about 50μm to about 1000 μm. In one embodiment, the decrease in Central FovealThickness is from about 50 μm to about 750 μm. In another embodiment,the decrease in Central Foveal Thickness is from about 200 μm to about1000 μm. In a further embodiment, the decrease in Central FovealThickness is from about 150 μm to about 500 μm. In a still furtherembodiment, the decrease in Central Foveal Thickness is from about 50 μmto about 500 μm. In a yet another embodiment, the decrease in CentralFoveal Thickness is from about 250 μm to about 650 μm. In a yet stillfurther embodiment, the decrease in Central Foveal Thickness is fromabout 200 μm to about 500 μm. In another still further embodiment, thedecrease in Central Foveal Thickness is from about 400 μm to about 700μm.

Further disclosed herein are methods for increasing the visual acuity ofa subject having a disease or condition as disclosed herein.

Visual Acuity

Visual acuity (VA) is acuteness or clearness of vision, which isdependent on the sharpness of the retinal focus within the eye and thesensitivity of the interpretative faculty of the brain. Visual acuity isa measure of the spatial resolution of the visual processing system. VAis tested by requiring the person whose vision is being tested toidentify characters typically numbers or letters on a chart from a setdistance. Chart characters are represented as black symbols against awhite background. The distance between the persons eyes and the testingchart is set at a sufficient distance to approximate infinity in the waythe lens attempts to focus. Twenty feet, or six meters, is essentiallyinfinity from an optical perspective. In the present disclosure, animprovement in visual acuity was assessed by an increase in the numberof letters read from the chart.

Visual Acuity Testing. One non-limiting test for measuring Visual Acuityis the use of the ESV-3000 ETDRS testing device (see, U.S. Pat. No.5,078,486) self-calibrated test lighting. The ESV-3000 deviceincorporates highly advanced LED light source technology. Theauto-calibration circuitry constantly monitors the LED light source andcalibrates the test luminance to 85 cd/m2 or 3 cd/m2.

Although designed for clinical trials where large-format ETDRS testing(up to 20/200) is performed at 4 meters, the device can be used in anon-research setting, i. e. , hospital or clinic where ocular diseasemonitoring is conducted. To properly evaluate ETDRS, the test should beconducted under standardized lighting conditions, for, example, photopictest level of 85 cd/m2. This light level has been recommended by theNational Academy of Sciences and by the American National StandardsInstitute for ETDRS and contrast sensitivity vision testing. Scoring ofvisual acuity can be accomplished in any manner chosen by the monitor.After providing a baseline evaluation, the increase or decrease in thenumber of letters that can be identified by the test subject provides ameasure of sight increase or decrease during treatment.

In one aspect, disclosed herein is a method for increasing visual acuityin a subject having a disease or condition of the eye as disclosedherein. This method comprises administering to a patient having adisease or condition of the eye:

-   -   a) a HPTP-β inhibitor or a pharmaceutically acceptable salt        thereof; and    -   b) one or more anti-VEGF agents;

A further embodiment of this aspect relates to a method for increasingvisual acuity in a subject, comprising administering to a patient havinga disease or condition of the eye:

-   -   a) a disclosed HPTP-β inhibitor or a pharmaceutically acceptable        salt thereof; and    -   b) one or more anti-VEGF agents;        wherein the administration of the HPTP-β inhibitor or a        pharmaceutically acceptable salt thereof and the anti-VEGF agent        can be conducted in any manner desired by the administrator, for        example, as further described herein.

In some embodiments, the disclosure provides a method for increasingvisual acuity, the method comprising administering to a subject in needthereof a compound disclosed herein.

In one embodiment, the method provides a method for increasing thenumber of letters recognizable by a treated eye form about 1 to about 30letters. In another embodiment, the number of letters recognizable isincreased from about 5 to about 25 letters. In a further embodiment, thenumber of letters recognizable is increased from about 5 to about 20letters. In another further embodiment, the number of lettersrecognizable is increased from about 5 to about 15 letters. In a stillfurther embodiment, the number of letters recognizable is increased fromabout 5 to about 10 letters. In a yet another embodiment, the number ofletters recognizable is increased from about 10 to about 25 letters. Ina yet still further embodiment, the number of letters recognizable isincreased from about 15 to about 25 letters. In yet still anotherembodiment, the number of letters recognizable is increased from about20 to about 25 letters. The increase in visual acuity can be about 1letter, about 5 letters, about 10 letters, about 15 letters, about 20letters, or about 25 letters.

EXAMPLE 35 Baseline Study for Determining the Effectiveness of theDisclosed Methods for Treating Ocular Diseases

Described herein below is a study of four human subjects with visualacuity loss due to diabetic macular edema (central retinal thickness[CRT] of more than 325 microns and best corrected visual acuity lessthan 70 letters) that were treated with subcutaneous injections of 5 mgof the4-{(S)-2-[(S)-2-methoxycarbonyl-amino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid twice a day for 28 days. Improvement of visual acuity in thesesubjects was observed for a period of two months (days 28 through 84).At any time during the course of the study, investigators couldadminister additional therapy consisting of intravitreal injection of ananti-VEGF agent, for example, ranibizumab, bevacizumab and/oraflibercept, if considered by the investigator to be medicallynecessary. Retinal thickness as measured by ocular coherence tomographyand best corrected visual acuity as measured by a standard vision test(ETDRS) were assessed at regular intervals during the 28 day activetreatment phase and through the 2 month post-treatment observationphase, (Screening, Day 1 [baseline], Day 7, Day 14, Day 21, Day 28, Day42, Day 56 and Day 84). The main efficacy outcomes for the study werechange in CRT and visual acuity over time with treatment.

FIG. 1 depicts the results of two phase three studies to determine theeffect of intravitreal injections of ranibizumab in patients withdiabetic macular edema. In this study patients received intravitrealinjections with either 0.3 mg (♦) or 0.5 mg (▪) ranibizumab monthly,whereas the control group (▴) received placebo. As depicted in FIG. 1the reduction in Central Foveal Thickness (CFT) for both the 0.3 mg and0.5 mg cohorts were essentially identical. As shown in FIG. 1, the twogroups receiving ranibizumab had a reduction in Central Foveal Thicknessof approximately 120 to 160 μm from day 7 to 1 month after the firstinjection of ranibizumab.

FIG. 2 depicts the results of a study wherein 4 patients received 5 mgof the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily for 28 days and subsequently weretreated in one or both eyes (7 eyes total) with either ranibizumab (0.3or 0.5 mg) or aflibercept (2 mg) by intravitreal injection at thediscretion of the study investigator. FIG. 2 is read in this manner 1patient eye had a Central Foveal Reduction of between 50-100 μm, 1patient eye had a Central Foveal Reduction of between 150-200 μm, 1patient eye had a Central Foveal Reduction of between 200-250 μm, 1patient eye had a Central Foveal Reduction of between 300-350 μm, 2patient eyes had a Central Foveal Reduction of between 350-400 μm, and 1patient eye had a Central Foveal Reduction of between 450-500 um at14-28 days post ranibizumab or aflibercept. The mean change in CentralFoveal Thickness was −289 μm, approximately double the reduction seenafter ranibizumab injection in the study in FIG. 1.

FIG. 3 depicts the results of two phase three studies performed todetermine the effect of intravitreal injections of ranibizumab inpatients with diabetic macular edema. Results of these studies were usedto determining the effectiveness of the disclosed methods for treatingocular diseases. The control group is represented by (♦). Patientsreceiving 0.5 mg of ranibizumab monthly via ocular injection arerepresented by (▪). As shown in FIG. 3, the group receiving ranibizumabhad an increase in visual acuity of between approximately 4 to 6 lettersfrom day 7 to 1 month after the first injection of ranibizumab.

FIG. 4 depicts the increased visual acuity of a study wherein 4 patientsreceived 5 mg of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily for 28 days and subsequently weretreated with either ranibizumab (0.3 or 0.5 mg) or aflibercept (2 mg) byintravitreal injection at the discretion of the study investigator. FIG.4 is read in this manner 1 patient eye had an increase of from 16 to 18letters improvement, 2 patient eyes had an increase of from 14 to 16letters improvement, 1 patient eye had an increase of from 10 to 12letters improvement, 1 patient eye had an increase of from 6 to 8letters improvement, 1 patient eye had an increase of from 2 to 4letters improvement, and 1 patient eye had a decrease of from 2 to 4letters at 14-28 days post ranibizumab or aflibercept. The mean changein Visual Acuity was 9 letters, approximately 3 to 5 letters moreimprovement than seen in the benchmark study of ranibizumab alonedepicted in FIG. 3.

FIG. 5 represents the results of a single patient. The eye having thegreater Central Foveal Thickness was chosen as the Study Eye. Thepatient from day one was given 5 mg of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily. At week 3 (21days, indicated by arrow)the fellow eye was treated with 0.5 mg of ranibizumab by injection. Atweek 6 (42 days, indicated by arrow) the treated eye was treated with0.5 mg of ranibizumab. As seen in FIG. 5, the Central Foveal Thicknessof the fellow eye fell significantly (350 μm) by week 4 (28 days). As aresult, there was a pronounced reduction in CFT in the study eye fromday 21 to day 28 (approximately 250 □m). As seen in FIG. 5, by the nextmonitoring point, week 6, the effects of the systemically receivedranibizumab were no longer present and the CFT returned to approximately775 μm. At week 6, the study eye was treated with an intravitrealinjection of 0.5 mg of ranibizumab. As depicted in FIG. 5, by week 8,there was an overall reduction in CFT of approximately 500 μm, whereinthe CFT of the subject eye was approximately 225 μm. Compared to thestudy depicted in FIG. 1 wherein the average change in CFT at one monthafter ranibizumab injection was approximately 160 mm, the combinationdisclosed method provided substantially greater reductions at 2-4 weeksfollowing ranibizumab injection.

FIG. 6 represents the results of a single patient. The eye having thegreater Central Foveal Thickness was chosen as the Study Eye. Thepatient from day one was given 5 mg of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily. At week 4 (28 days, indicated by arrow)the fellow eye was rescued with 2 mg of aflibercept. After rescue, theFellow eye had a CFT reduction of approximately 400 μm. At week 6 (42days, indicated by arrow) the study eye was rescued with 2 mg ofaflibercept. After rescue, the Study eye had a CFT reduction ofapproximately 300 μm. Unlike the results depicted for the ranibizumabprotocol, there was no evidence of systemically delivered aflibercept tothe Fellow Eye. From onset of the study, there was a reduction of CFT inthe study eye and non-treated eye of approximately 300 μm and 280 μmrespectively.

FIG. 7 graphically represents the results of a choroidalneovascularization murine test involving an active control, aflibercept(Eylea™), the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid and a combination of aflibercept and the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid . Rupture of Burch's membrane in three locations of the eye wasinduced by standard laser methods (see, Tobe T et al., “TargetedDisruption of the FGF2 Gene Does Not Prevent ChoroidalNeovascularization in a Murine Model,” Am. J. Pathology, Vol. 153, No.5, (1998)). Control animals were given intraocular injections ofphosphate buffered saline (PBS), animals treated with afliberceptreceived one intraocular 40 μg of the drug on the day of lasertreatment. The mice were then treated with either the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid at 20 mg/kg by subcutaneous injections twice daily or PBSinjections twice daily. This yielded four groups of mice; a negativecontrol group treated with intraocular and subcutaneous PBS, amonotherapy group treated with intraocular aflibercept and subcutaneousPBS, a monotherapy group treated with intraocular PBS and subcutaneousinjections of the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid and a combination therapy group receiving one intraocular injectionof 40 μg of the drug on the day of laser treatment and 20 mg/kgsubcutaneous injections twice daily.

FIG. 8A-D depicts the flat mounts of excised choroidal tissue stainedwith FITC-labeled Griffonia simplicifolia (GSA). The extent of choroidalneovascular is evident in the control sample FIG. 8A. FIG. 8B representsthe extent of neovascularization in the choroidal tissue of animalstreated with aflibercept, FIG. 8C represents animals treated with thedisclosed Tie-2 signaling enhancer and FIG. 8D represents the extent ofneovascularization present in animals having a combined therapy ofaflibercept and the4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid.

EXAMPLE 36 Solubility of Compounds of the Disclosure.

The room temperature aqueous solubility (mg/mL) of the a compound(4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid) in water, HPβCD, Poloxamer 407, andsulfobutylether-β-cyclodextrin, is provided in TABLE XXVII. Solubilityin saline for the test compound is reduced presumably due to the commonion effect. All the solubilizing agents tested provided goodimprovements in aqueous solubility of the test compound.

TABLE XXVII Solubility % HPβCD  0 27 10 45 20 57 30 72 % SBE-B-CD 15 44% Poloxamer 407 20 44

The solubility (mg/mL) of the test compound in mixtures of HPβCD andPEG400 is illustrated in TABLE XXVIII. Use of either HPβCD or PEG400individually provided an increase in solubility. However, addition ofPEG400 to a mixture of the test compound and HPβCD caused an erosion ofsolubility, with solubility being inversely proportional to the amountof PEG400.

TABLE XXVIII % HPβCD % PEG400 Solubility 0 15 30 0 30 68 15 0 59 15 5 5715 10 34 15 15 6

TABLE XXIX contains aqueous solution formulations of the test compoundabove with the denoted solvents that have been prepared and shown to bechemically stable through 1 month at 50° C., and physically stable at 5°C., at ambient temperature, and at 50° C. The formulations are morestable at pH values above pH 4. The target pH range for the formulationsis pH 7+/−0.5 pH units.

TABLE XXIX Formulation Concentration of test compound 10% HPβCD 15 mg/mL25% HPβCD 50 mg/mL 30% HPβCD 50 mg/mL 15% HPβCD/0.25% saline 40mg/mL^(a) 4.5% mannitol 5 mg/mL^(b) ^(a)Evaluated for short-termphysical stability at 5° C. and ambient temperature. ^(b)Physically andchemically stable through one week at room temperature and one week at50° C.

TABLE XXX shows the solubility (mg/mL) of two compounds with varyingconcentrations of HPβCD. TABLE XXX shows that 25% HPβCD almost doublesthe solubility of the test compounds when compared to their solubilityin pure water.

TABLE XXX

% HPβCD Solubility Solubility  0 38 45  5 42 60 15 60 NT 25 74 89

Pharmacokinetic and Pharmacodynamic Measurements. EXAMPLE 37 PlasmaConcentration in Human Test Subjects.

FIG. 9 depicts the mean plasma concentration over time after a singledose of a 5 mg, a 15 mg, a 22.5 mg, or a 30 mg of a test compound on day14, respectively, in a multiple ascending dose study in patients withdiabetic macular edema. The concentration time curves are consistentwith rapid absorption and elimination of test compound with rapid Tmax(range 0.2 to 1.0 hours) and short elimination half-life (range 0.6 to1.5 hours). The overall exposures were approximately dose proportionalwith Cmax ranging from approximately 40-430 ng/ml and AUC ranging fromapproximately 70 — 920 ng. hr/ml at 5-30 mg dose.

EXAMPLE 38 Phase 1B/2A Clinical Trial.

A phase 1B/2A open-label, Multiple-ascending dose cohort study to assessthe pharmacokinetics and pharmacodynamics effect of 28-day repeatsubcutaneous dose of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (drug) in subjects with diffuse diabetic macular edema (DME).

The aim of this study was to evaluate tolerability, safety, efficacy andpharmacokinetics and pharmacodynamics in patients with DME involving thecenter of the fovea with central subfield mean thickness ≥325μm measuredby spectral domain-optical coherence tomography (SD-OCT).

Twenty-four patients were administered ascending doses of test compoundtwice daily (BID) for 28 days in 4 separate cohorts at 5, 15, 22.5 or 30mg BID, respectively.

Drug was supplied as a lyophilized powder in a vial for reconstitution.Each vial contained 100 mg drug and 250 mg HPβCD. Vials werereconstituted with sterile 5% dextrose for cohort 1 (5 mg BID) and withsterile diluent containing 5% HPβCD/1% dextrose for cohorts 2, 3, and 4(15 mg, 22.5 mg and 30 mg BID).

For cohorts 1 (5 mg BID) and 2 (15 mg BID) the volume administered foreach dose was 0.5 ml (10 and 30 mg/ml, respectively) and for cohorts 3and 4 the volume was 0.75 ml (30 and 40 mg/ml, respecitvely).

Blood samples for pharmacokinetic profiling were taken pre-dose(O), 15minutes, 1 hour, 2 hours, 3 hours and 4 hours after administration ofthe first dose on day 14.

Plasma drug concentration was determined with a validated LC/MS-MSmethod. The pharmacokinetic (PK) parameters were determined using astandard non-comparmental method, and Cmax, AUC_(last) (with last beingfrom time 0 to the last quantifiable point), AUCinf, were analyzedstatistically using log-transformed data. The dose proportionality 90%confidence intervals were calculated from the mean.

The PK/PD parameter data and statistical analyses are provided in TablesXXXI to XXXV (Day 14). FIG. 9 shows the drug plasma concentration overtime for Day 14.

Day 14 PK/PD Parameters

TABLE XXXI 5 mg BID 15 mg BID 22.5 mg BID 30 mg BID Day 14 (N = 6) (N =6) (N = 5) (N = 7) C_(max) (ng/mL) N 6 6 4 6 Mean (SD) 77.75 156.57237.40 320.48 (24.103) (51.767) (122.075) (68.471) Median 73.44 138.05203.20 320.85 Min-Max 44.7-108.1 102.5-226.3 142.7-400.5 220.9-426.1 %CV 31.0 33.1 51.4 21.4 Geometric Mean 74.48 149.86 215.72 314.24Geometric % CV 33.6 32.9 53.3 22.2 Power Model of Dose ProportionalitySlope 0.815 Standard Error 0.1009 90% CI (0.602, 0.950)

TABLE XXXII 5 mg BID 15 mg BID 22.5 mg BID 30 mg BID t_(max) (hr) (N =6) (N = 6) (N = 5) (N = 7) N 6 6 4 6 Mean (SD) 0.31 0.27 0.45 0.63(0.134) (0.039) (0.370) (0.391) Median 0.26 0.25 0.27 0.64 Min-Max0.3-0.6 0.2-0.3 0.3-1.0 0.2-1.0 % CV 42.9 14.3 82.9 62.3

TABLE XXXIII 5 mg BID 15 mg BID 22.5 mg BID 30 mg BID Day 14 (N = 6) (N= 6) (N = 5) (N = 7) AUC_(last) (ng · hr/mL) N 6 6 4 6 Mean (SD) 101.56239.08 437.51 669.37 (26.956) (71.302) (235.327) (130.226) Median 97.03213.32 328.84 700.90 Min-Max 67.9-142.6 170.4-353.3 302.7-789.6444.1-796.1 % CV 26.5 29.8 53.8 19.5 Geometric Mean 98.63 230.97 400.80657.33 Geometric % CV 27.0 28.8 47.9 21.9 Power Model of DoseProportionality Slope 1.021 Standard Error 0.0966 90% CI (0.854, 1.187)

TABLE XXXIV 5 mg BID 15 mg BID 22.5 mg BID 30 mg BID Day 14 (N = 6) (N =6) (N = 5) (N = 7) AUC_(inf) (ng · hr/mL) N 6 6 3 3 Mean (SD) 106.46255.08 498.12 828.62 (30.665) (78.518) (273.956) (95.996) Median 100.55232.89 358.19 834.70 Min-Max 70.1-155.1 176.8-387.4 322.4-813.8729.7-921.4 % CV 28.8 30.8 55.0 11.6 Geometric Mean 102.92 245.89 454.63824.87 Geometric % CV 29.0 29.8 54.1 11.7 Power Model of DoseProportionality Slope 1.056 Standard Error 0.1174 90% CI (0.851, 1.261)

TABLE XXXV 5 mg BID 15 mg BID 22.5 mg BID 30 mg BID Day 14 (N = 6) (N =6) (N = 5) (N = 7) t_(1/2) (hr) N 6 6 3 3 Mean (SD) 0.85 0.96 0.84 1.07(0.186) (0.282) (0.093) (0.338) Median 0.83 0.89 0.87 0.93 Min-Max0.6-1.1 0.6-1.4 0.7-0.9 0.8-1.5 % CV 21.9 29.5 11.0 31.4

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 80 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean AUC_(last) of the HPTP-β inhibitor is within 70% to130% of an AUC_(last) of 100 ng.hr/ml, after administration of a singledose of the HPTP-β inhibitor to a human

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean AUC_(last) of the HPTP-β inhibitor is within 70% to130% of an AUC_(inf) of 100 ng.hr/ml, after administration of a singledose of the HPTP-β inhibitor to a human

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean t_(1/2) of the HPTP-β inhibitor is within 70% to 130%of a t_(1/2) of 1 hour, after administration of a single dose of theHPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 80 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean AUC_(last) of theHPTP-β inhibitor is within 70% to 130% of an AUC_(last) of 100 ng.hr/ml,after administration of a single dose of the HPTP-β inhibitor to a human

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 80 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean AUC_(last) of theHPTP-β inhibitor is within 70% to 130% of an AUC_(inf) of 100 ng.hr/ml,after administration of a single dose of the HPTP-β inhibitor to ahuman.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 80 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean t_(1/2) of the HPTP-βinhibitor is within 70% to 130% of a t_(1/2) of 1 hour, afteradministration of a single dose of the HPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 150 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean AUC_(last) of the HPTP-β inhibitor is within 70% to130% of an AUC_(last) of 217 ng.hr/ml, after administration of a singledose of the HPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean AUC_(last) of the HPTP-β inhibitor is within 70% to130% of an AUC_(inf) of 255 ng.hr/ml, after administration of a singledose of the HPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 150ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean AUC_(last) of theHPTP-β inhibitor is within 70% to 130% of an AUC_(last) of 217 ng.hr/ml,after administration of a single dose of the HPTP-β inhibitor to ahuman.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 150 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean AUC_(last) of theHPTP-β inhibitor is within 70% to 130% of an AUC_(inf) of 255 ng.hr/ml,after administration of a single dose of the HPTP-β inhibitor to ahuman.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 150 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean t_(1/2) of the HPTP-βinhibitor is within 70% to 130% of a t_(1/2) of 1 hour, afteradministration of a single dose of the HPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 240 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean AUC_(last) of the HPTP-β inhibitor is within 70% to130% of an AUC_(last) of 440 ng.hr/ml, after administration of a singledose of the HPTP-β inhibitor to a human

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean AUC_(last) of the HPTP-β inhibitor is within 70% to130% of an AUC_(inf) of 500 ng.hr/ml, after administration of a singledose of the HPTP-β inhibitor to a human

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 240 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean AUC_(last) of theHPTP-β inhibitor is within 70% to 130% of an AUC_(last) of 440ng.hr/ml,after administration of a single dose of the HPTP-β inhibitor to ahuman.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 240 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean AUC_(last) of theHPTP-β inhibitor is within 70% to 130% of an AUC_(inf) of 500 ng.hr/ml,after administration of a single dose of the HPTP-β inhibitor to a human

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 240 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean t_(1/2) of the HPTP-βinhibitor is within 70% to 130% of a t_(1/2) of 1 hour, afteradministration of a single dose of the HPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 300 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean AUC_(last) of the HPTP-β inhibitor is within 70% to130% of an AUC_(last) of 640 ng.hr/ml, after administration of a singledose of the HPTP-β inhibitor to a human

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean AUC_(last) of the HPTP-β inhibitor is within 70% to130% of an AUC_(inf) of 830 ng.hr/ml, after administration of a singledose of the HPTP-β inhibitor to a human

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 300 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean AUC_(last) of theHPTP-β inhibitor is within 70% to 130% of an AUC_(last) of 640 ng.hr/ml,after administration of a single dose of the HPTP-β inhibitor to a human

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 300 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean AUC_(last) of theHPTP-β inhibitor is within 70% to 130% of an AUC_(inf) of 830 ng.hr/ml,after administration of a single dose of the HPTP-β inhibitor to ahuman.

In some embodiments, the invention provides a pharmaceutical compositionin unit dose form for subcutaneously delivery of a compositioncomprising an HPTP-β inhibitor and 2- hydroxypropyl-β-cyclodextrinwherein the mean C_(max) of the HPTP-β inhibitor is within 70% to 130%of a C_(max) of 300 ng/ml, after administration of a single dose of theHPTP-β inhibitor to a human; and wherein the mean t_(1/2) of the HPTP-βinhibitor is within 70% to 130% of a t_(1/2) of 1 hour, afteradministration of a single dose of the HPTP-β inhibitor to a human.

In some embodiments, the HPTP-β inhibitor is4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid.

In some embodiments, the HPTP-β inhibitor is(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthiazol-2-yl]ethyl}phenyl)sulfamicacid.

In some embodiments, the HPTP-β inhibitor is4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid.

In some embodiments, the HPTP-β inhibitor is(4-((8)-2-((S)-2-((methoxycarbonyl)amino)-3-phenylpropanamido)-2-(4-(thiophen-2-yl)thiazol-2-yl)ethyl)phenyl)sulfamicacid.

A dose can be modulated to achieve a desired pharmacokinetic orpharmacodynamics profile, such as a desired or effective blood profile,as described herein.

Pharmacokinetic and pharmacodynamic data can be obtained by variousexperimental techniques. Appropriate pharmacokinetic and pharmacodynamicprofile components describing a particular composition can vary due tovariations in drug metabolism in human subjects. Pharmacokinetic andpharmacodynamic profiles can be based on the determination of the meanparameters of a group of subjects. The group of subjects includes anyreasonable number of subjects suitable for determining a representativemean, for example, 5 subjects, 10 subjects, 15 subjects, 20 subjects, 25subjects, 30 subjects, 35 subjects, or more. The mean is determined, forexample, by calculating the average of all subject's measurements foreach parameter measured. A dose can be modulated to achieve a desiredpharmacokinetic or pharmacodynamics profile, such as a desired oreffective blood profile, as described herein.

The pharmacodynamic parameters can be any parameters suitable fordescribing compositions of the invention. For example, thepharmacodynamic profile can be obtained at a time after dosing of, forexample, about zero minutes, about 1 minute, about 2 minutes, about 3minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39minutes, about 40 minutes, about 41 minutes, about 42 minutes, about 43minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59minutes, about 60 minutes, about zero hours, about 0.5 hours, about 1hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours,about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours,about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours,about 12 hours, about 12.5 hours, about 13 hours, about 13.5 hours,about 14 hours, about 14.5 hours, about 15 hours, about 15.5 hours,about 16 hours, about 16.5 hours, about 17 hours, about 17.5 hours,about 18 hours, about 18.5 hours, about 19 hours, about 19.5 hours,about 20 hours, about 20.5 hours, about 21 hours, about 21.5 hours,about 22 hours, about 22.5 hours, about 23 hours, about 23.5 hours, orabout 24 hours.

The pharmacokinetic parameters can be any parameters suitable fordescribing a compound. The C_(max) can be, for example, not less thanabout 1 ng/mL; not less than about 5 ng/mL; not less than about 10ng/mL; not less than about 15 ng/mL; not less than about 20 ng/mL; notless than about 25 ng/mL; not less than about 50 ng/mL; not less thanabout 75 ng/mL; not less than about 100 ng/mL; not less than about 200ng/mL; not less than about 300 ng/mL; not less than about 400 ng/mL; notless than about 500 ng/mL; not less than about 600 ng/mL; not less thanabout 700 ng/mL; not less than about 800 ng/mL; not less than about 900ng/mL; not less than about 1000 ng/mL; not less than about 1250 ng/mL;not less than about 1500 ng/mL; not less than about 1750 ng/mL; not lessthan about 2000 ng/mL; or any other C_(max) appropriate for describing apharmacokinetic profile of a compound described herein. The C_(max) canbe, for example, about 1 ng/mL to about 5,000 ng/mL; about 1 ng/mL toabout 4,500 ng/mL; about 1 ng/mL to about 4,000 ng/mL; about 1 ng/mL toabout 3,500 ng/mL; about 1 ng/mL to about 3,000 ng/mL; about 1 ng/mL toabout 2,500 ng/mL; about 1 ng/mL to about 2,000 ng/mL; about 1 ng/mL toabout 1,500 ng/mL; about 1 ng/mL to about 1,000 ng/mL; about 1 ng/mL toabout 900 ng/mL; about 1 ng/mL to about 800 ng/mL; about 1 ng/mL toabout 700 ng/mL; about 1 ng/mL to about 600 ng/mL; about 1 ng/mL toabout 500 ng/mL; about 1 ng/mL to about 450 ng/mL; about 1 ng/mL toabout 400 ng/mL; about 1 ng/mL to about 350 ng/mL; about 1 ng/mL toabout 300 ng/mL; about 1 ng/mL to about 250 ng/mL; about 1 ng/mL toabout 200 ng/mL; about 1 ng/mL to about 150 ng/mL; about 1 ng/mL toabout 125 ng/mL; about 1 ng/mL to about 100 ng/mL; about 1 ng/mL toabout 90 ng/mL; about 1 ng/mL to about 80 ng/mL; about 1 ng/mL to about70 ng/mL; about 1 ng/mL to about 60 ng/mL; about 1 ng/mL to about 50ng/mL; about 1 ng/mL to about 40 ng/mL; about 1 ng/mL to about 30 ng/mL;about 1 ng/mL to about 20 ng/mL; about 1 ng/mL to about 10 ng/mL; about1 ng/mL to about 5 ng/mL; about 10 ng/mL to about 4,000 ng/mL; about 10ng/mL to about 3,000 ng/mL; about 10 ng/mL to about 2,000 ng/mL; about10 ng/mL to about 1,500 ng/mL; about 10 ng/mL to about 1,000 ng/mL;about 10 ng/mL to about 900 ng/mL; about 10 ng/mL to about 800 ng/mL;about 10 ng/mL to about 700 ng/mL; about 10 ng/mL to about 600 ng/mL;about 10 ng/mL to about 500 ng/mL; about 10 ng/mL to about 400 ng/mL;about 10 ng/mL to about 300 ng/mL; about 10 ng/mL to about 200 ng/mL;about 10 ng/mL to about 100 ng/mL; about 10 ng/mL to about 50 ng/mL;about 25 ng/mL to about 500 ng/mL; about 25 ng/mL to about 100 ng/mL;about 50 ng/mL to about 500 ng/mL; about 50 ng/mL to about 100 ng/mL;about 100 ng/mL to about 500 ng/mL; about 100 ng/mL to about 400 ng/mL;about 100 ng/mL to about 300 ng/mL; or about 100 ng/mL to about 200ng/mL.

The T_(max) of a compound described herein can be, for example, notgreater than about 0.5 hours, not greater than about 1 hours, notgreater than about 1.5 hours, not greater than about 2 hours, notgreater than about 2.5 hours, not greater than about 3 hours, notgreater than about 3.5 hours, not greater than about 4 hours, notgreater than about 4.5 hours, not greater than about 5 hours, or anyother T_(max) appropriate for describing a pharmacokinetic profile of acompound described herein. The T_(max) can be, for example, about 0.1hours to about 24 hours; about 0.1 hours to about 0.5 hours; about 0.5hours to about 1 hour; about 1 hour to about 1.5 hours; about 1.5 hoursto about 2 hour; about 2 hours to about 2.5 hours; about 2.5 hours toabout 3 hours; about 3 hours to about 3.5 hours; about 3.5 hours toabout 4 hours; about 4 hours to about 4.5 hours; about 4.5 hours toabout 5 hours; about 5 hours to about 5.5 hours; about 5.5 hours toabout 6 hours; about 6 hours to about 6.5 hours; about 6.5 hours toabout 7 hours; about 7 hours to about 7.5 hours; about 7.5 hours toabout 8 hours; about 8 hours to about 8.5 hours; about 8.5 hours toabout 9 hours; about 9 hours to about 9.5 hours; about 9.5 hours toabout 10 hours; about 10 hours to about 10.5 hours; about 10.5 hours toabout 11 hours; about 11 hours to about 11.5 hours; about 11.5 hours toabout 12 hours; about 12 hours to about 12.5 hours; about 12.5 hours toabout 13 hours; about 13 hours to about 13.5 hours; about 13.5 hours toabout 14 hours; about 14 hours to about 14.5 hours; about 14.5 hours toabout 15 hours; about 15 hours to about 15.5 hours; about 15.5 hours toabout 16 hours; about 16 hours to about 16.5 hours; about 16.5 hours toabout 17 hours; about 17 hours to about 17.5 hours; about 17.5 hours toabout 18 hours; about 18 hours to about 18.5 hours; about 18.5 hours toabout 19 hours; about 19 hours to about 19.5 hours; about 19.5 hours toabout 20 hours; about 20 hours to about 20.5 hours; about 20.5 hours toabout 21 hours; about 21 hours to about 21.5 hours; about 21.5 hours toabout 22 hours; about 22 hours to about 22.5 hours; about 22.5 hours toabout 23 hours; about 23 hours to about 23.5 hours; or about 23.5 hoursto about 24 hours.

The AUC_((0-inf)) or AUC(_(last)) of a compound described herein can be,for example, not less than about 1 ng.hr/mL, not less than about 5ng.hr/mL, not less than about 10 ng.hr/mL, not less than about 20ng.hr/mL, not less than about 30 ng.hr/mL, not less than about 40ng.hr/mL, not less than about 50 ng.hr/mL, not less than about 100ng.hr/mL, not less than about 150 ng.hr/mL, not less than about 200ng.hr/mL, not less than about 250 ng.hr/mL, not less than about 300ng.hr/mL, not less than about 350 ng.hr/mL, not less than about 400ng.hr/mL, not less than about 450 ng.hr/mL, not less than about 500ng.hr/mL, not less than about 600 ng.hr/mL, not less than about 700ng.hr/mL, not less than about 800 ng.hr/mL, not less than about 900ng.hr/mL, not less than about 1000 ng.hr/mL, not less than about 1250ng.hr/mL, not less than about 1500 ng.hr/mL, not less than about 1750ng.hr/mL, not less than about 2000 ng.hr/mL, not less than about 2500ng.hr/mL, not less than about 3000 ng.hr/mL, not less than about 3500ng.hr/mL, not less than about 4000 ng.hr/mL, not less than about 5000ng.hr/mL, not less than about 6000 ng.hr/mL, not less than about 7000ng.hr/mL, not less than about 8000 ng.hr/mL, not less than about 9000ng.hr/mL, not less than about 10,000 ng.hr/mL, or any otherAUC_((0-inf)) appropriate for describing a pharmacokinetic profile of acompound described herein. The AUC_((0-inf)) of a compound can be, forexample, about 1 ng.hr/mL to about 10,000 ng.hr/mL; about 1 ng.hr/mL toabout 10 ng.hr/mL; about 10 ng.hr/mL to about 25 ng.hr/mL; about 25ng.hr/mL to about 50 ng.hr/mL; about 50 ng.hr/mL to about 100 ng.hr/mL;about 100 ng.hr/mL to about 200 ng.hr/mL; about 200 ng.hr/mL to about300 ng.hr/mL; about 300 ng.hr/mL to about 400 ng.hr/mL; about 400ng.hr/mL to about 500 ng.hr/mL; about 500 ng.hr/mL to about 600ng.hr/mL; about 600 ng.hr/mL to about 700 ng.hr/mL; about 700 ng.hr/mLto about 800 ng.hr/mL; about 800 ng.hr/mL to about 900 ng.hr/mL; about900 ng.hr/mL to about 1,000 ng.hr/mL; about 1,000 ng.hr/mL to about1,250 ng.hr/mL; about 1,250 ng.hr/mL to about 1,500 ng.hr/mL; about1,500 ng.hr/mL to about 1,750 ng.hr/mL; about 1,750 ng.hr/mL to about2,000 ng.hr/mL; about 2,000 ng.hr/mL to about 2,500 ng.hr/mL; about2,500 ng.hr/mL to about 3,000 ng.hr/mL; about 3,000 ng.hr/mL to about3,500 ng.hr/mL; about 3,500 ng.hr/mL to about 4,000 ng.hr/mL; about4,000 ng.hr/mL to about 4,500 ng.hr/mL; about 4,500 ng.hr/mL to about5,000 ng.hr/mL; about 5,000 ng.hr/mL to about 5,500 ng.hr/mL; about5,500 ng.hr/mL to about 6,000 ng.hr/mL; about 6,000 ng.hr/mL to about6,500 ng.hr/mL; about 6,500 ng.hr/mL to about 7,000 ng.hr/mL; about7,000 ng.hr/mL to about 7,500 ng.hr/mL; about 7,500 ng.hr/mL to about8,000 ng.hr/mL; about 8,000 ng.hr/mL to about 8,500 ng.hr/mL; about8,500 ng.hr/mL to about 9,000 ng.hr/mL; about 9,000 ng.hr/mL to about9,500 ng.hr/mL; or about 9,500 ng.hr/mL to about 10,000 ng.hr/mL.

The plasma concentration of a compound described herein can be, forexample, not less than about 1 ng/mL, not less than about 5 ng/mL, notless than about 10 ng/mL, not less than about 15 ng/mL, not less thanabout 20 ng/mL, not less than about 25 ng/mL, not less than about 50ng/mL, not less than about 75 ng/mL, not less than about 100 ng/mL, notless than about 150 ng/mL, not less than about 200 ng/mL, not less thanabout 300 ng/mL, not less than about 400 ng/mL, not less than about 500ng/mL, not less than about 600 ng/mL, not less than about 700 ng/mL, notless than about 800 ng/mL, not less than about 900 ng/mL, not less thanabout 1000 ng/mL, not less than about 1200 ng/mL, or any other plasmaconcentration of a compound described herein. The plasma concentrationcan be, for example, about 1 ng/mL to about 2,000 ng/mL; about 1 ng/mLto about 5 ng/mL; about 5 ng/mL to about 10 ng/mL; about 10 ng/mL toabout 25 ng/mL; about 25 ng/mL to about 50 ng/mL; about 50 ng/mL toabout 75 ng/mL; about 75 ng/mL to about 100 ng/mL; about 100 ng/mL toabout 150 ng/mL; about 150 ng/mL to about 200 ng/mL; about 200 ng/mL toabout 250 ng/mL; about 250 ng/mL to about 300 ng/mL; about 300 ng/mL toabout 350 ng/mL; about 350 ng/mL to about 400 ng/mL; about 400 ng/mL toabout 450 ng/mL; about 450 ng/mL to about 500 ng/mL; about 500 ng/mL toabout 600 ng/mL; about 600 ng/mL to about 700 ng/mL; about 700 ng/mL toabout 800 ng/mL; about 800 ng/mL to about 900 ng/mL; about 900 ng/mL toabout 1,000 ng/mL; about 1,000 ng/mL to about 1,100 ng/mL; about 1,100ng/mL to about 1,200 ng/mL; about 1,200 ng/mL to about 1,300 ng/mL;about 1,300 ng/mL to about 1,400 ng/mL; about 1,400 ng/mL to about 1,500ng/mL; about 1,500 ng/mL to about 1,600 ng/mL; about 1,600 ng/mL toabout 1,700 ng/mL; about 1,700 ng/mL to about 1,800 ng/mL; about 1,800ng/mL to about 1,900 ng/mL; or about 1,900 ng/mL to about 2,000 ng/mL.

The pharmacodynamic parameters can be any parameters suitable fordescribing compositions of the disclosure. For example, thepharmacodynamic profile can exhibit decreases in viability phenotype forthe tumor cells or tumor size reduction in tumor cell lines or xenograftstudies, for example, about 24 hours, about 48 hours, about 72 hours, or1 week.

Non-limiting examples of pharmacodynamic and pharmacokinetic parametersthat can be calculated for a compound that is administered with themethods of the invention include: a) the amount of drug administered,which can be represented as a dose D; b) the dosing interval, which canbe represented as r; c) the apparent volume in which a drug isdistributed, which can be represented as a volume of distribution V_(d),where V_(d)=D/C₀; d) the amount of drug in a given volume of plasma,which can be represented as concentration C₀ or C_(ss), where C₀ orC_(ss)=D/Vd and can be represented as a mean plasma concentration over aplurality of samples; e) the half-life of a drug t_(1/2), wheret_(1/2)=ln(2)/k_(e); f) the rate at which a drug is removed from thebody k_(e), where k_(e) =ln(2)/t_(1/2)=CL/V_(d); g) the rate of infusionrequired to balance the equation K_(in), where K_(in)=C_(ss). CL; h) theintegral of the concentration-time curve after administration of asingle dose, which can be represented as AUC_(0-∞), wherein ∫₀ ^(∞) Cdt, or in steady-state, which can be represented as AUCτ, _(ss), wherein∫_(τ) ^(t+)C dt; i) the volume of plasma cleared of the drug per unittime, which can be represented as CL (clearance), whereinCL=V_(d).k_(e)=D/AUC; j) the systemically available fraction of a drug,which can be represented as f, where

${f = \frac{{AUCpo} \cdot {Div}}{{AUCiv} \cdot {Dpo}}};$

k) LUC peak plasma concentration of a drug after administrationC_(max); 1) the time taken by a drug to reach C_(max), t_(max); m) thelowest concentration that a drug reaches before the next dose isadministered C_(min); and n) the peak trough fluctuation within onedosing interval at steady state, which can be represented as

${\%{PTF}} = {{{100 \cdot \frac{\left( {{Cmax},{{ss} - {Cmin}},{ss}} \right)}{{Cav},{ss}}}{where}C_{{av},{ss}}} = {\frac{{AUC\tau},{ss}}{\tau}.}}$

Embodiments

The following are illustrative embodiments.

-   Embodiment A1. A method of treating a condition in a subject in need    thereof, the method comprising administering to the subject a    therapeutically-effective amount of a compound that activates Tie-2,    or a pharmaceutically-acceptable salt thereof, and an agent that    increases solubility of the compound that activates Tie-2, or the    pharmaceutically-acceptable salt thereof as compared to solubility    in absence of the agent.-   Embodiment A2. The method of embodiment A1, wherein the compound    that activates Tie-2 or the pharmaceutically-acceptable salt thereof    binds HPTP-beta.-   Embodiment A3.The method of embodiment A1, wherein the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    inhibits HPTP-beta.-   Embodiment A4.The method of embodiment A1, wherein the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof is a    phosphate mimetic.-   Embodiment A5.The method of embodiment A1, wherein the compound that    activates Tie-2 comprises an amino acid backbone.-   Embodiment A6.The method of embodiment A1, wherein the compound that    activates Tie-2 comprises a sulfamic acid.-   Embodiment A7. The method of embodiment A1, wherein the agent that    improves the aqueous solubility of the compound that activates Tie-2    or the pharmaceutically-acceptable salt thereof comprises a polymer.-   Embodiment A8. The method of embodiment A1, wherein the agent that    improves the aqueous solubility of the compound that activates Tie-2    or the pharmaceutically-acceptable salt thereof comprises a    poly-ethylene glycol moiety.-   Embodiment A9. The method of embodiment A1, wherein the agent that    improves the aqueous solubility of the compound that activates Tie-2    or the pharmaceutically-acceptable salt thereof comprises a    cyclodextrin moiety.-   Embodiment A10. The method of embodiment A1, wherein the agent that    improves the aqueous solubility of the compound that activates Tie-2    or the pharmaceutically-acceptable salt thereof comprises a    2-hydroxypropyl-β-cyclodextrin moiety.-   Embodiment A11. The method of embodiment A1, wherein the agent that    improves the aqueous solubility of the compound that activates Tie-2    or the pharmaceutically-acceptable salt thereof comprises a    sulfobutylether-β-cyclodextrin moiety.-   Embodiment A12. The method of embodiment A1, wherein the compound    that activates Tie-2, or the pharmaceutically-acceptable salt    thereof, and the agent that improves the aqueous solubility of the    compound that activates Tie-2 or the pharmaceutically-acceptable    salt thereof are held in a complex by non-covalent interactions.-   Embodiment A13. The method of embodiment A1, wherein the agent that    improves the aqueous solubility of the compound that activates Tie-2    or the pharmaceutically-acceptable salt thereof comprises a    surfactant moiety.-   Embodiment A14. The method of embodiment A1, wherein the agent that    increases solubility of the compound that activates Tie-2 or the    pharmaceutically-acceptable salt thereof increases aqueous    solubility by at least 10% at each of 5° C., ambient temperature,    and 50° C.-   Embodiment A15. The method of embodiment A1, wherein the agent that    increases solubility of the compound that activates Tie-2 or the    pharmaceutically-acceptable salt thereof increases aqueous    solubility by at least 25%.-   Embodiment A16. The method of embodiment A1, wherein the agent that    increases solubility of the compound that activates Tie-2 or the    pharmaceutically-acceptable salt thereof increases aqueous    solubility by at least 50%.-   Embodiment A17. The method of embodiment A1, wherein the    therapeutically-effective amount is from about 0.1 mg to about 100    mg.-   Embodiment A18. The method of embodiment A1, wherein the    therapeutically-effective amount is from about 0.5 mg to about 30    mg.-   Embodiment A19. The method of embodiment A1, wherein the compound    that activates Tie-2, or the pharmaceutically-acceptable salt    thereof, and the agent that improves the aqueous solubility of the    compound that activates Tie-2 or the pharmaceutically-acceptable    salt thereof are coadministered in a unit dosage form.-   Embodiment A20. The method of embodiment A19, wherein the unit    dosage form is administered subcutaneously.-   Embodiment A21. The method of embodiment A19, wherein the unit    dosage form is administered to an eye.-   Embodiment A22. The method of embodiment A1, wherein the condition    is an ocular condition.-   Embodiment A23. The method of embodiment A1, wherein the condition    is diabetic macular edema.-   Embodiment A24. The method of embodiment A1, wherein the condition    is diabetic retinopathy.-   Embodiment A25. The method of embodiment A1, wherein the condition    is macular degeneration.-   Embodiment A26. The method of embodiment A1, wherein the condition    is vascular leak.-   Embodiment A27. The method of embodiment A1, wherein the condition    is a cancer.-   Embodiment A28. The method of embodiment A1, wherein the subject is    a human.-   Embodiment A29. The method of embodiment A1, wherein the subject's    visual acuity improves by at least 5 letters.-   Embodiment A30. The method of embodiment A1, wherein the compound    that activates Tie-2 is a compound of the formula:

wherein aryl¹ is an aryl group which is substituted or unsubstituted,aryl² is an aryl group which is substituted or unsubstituted, X isalkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, anamide linkage, an ester linkage, a thioether linkage, a carbamatelinkage, a carbonate linkage, a urethane linkage, a sulfone linkage, anyof which is substituted or unsubstituted, or a chemical bond, and Y isH, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g),any of which is substituted or unsubstituted, or

wherein L² is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a urethanelinkage, or a sulfonamide linkage, or a chemical bond, or together withany of R^(a), R^(b), R^(c), and R^(d) forms a ring that is substitutedor unsubstituted. R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L²,R^(b), R^(c), and R^(d) forms a ring that is substituted orunsubstituted. R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L²,R^(a), R^(c), and R^(d) forms a ring that is substituted orunsubstituted. R^(c) is H or alkyl which is substituted orunsubstituted, or together with any of L², R^(a), R^(b), and R^(d) formsa ring that is substituted or unsubstituted. R^(d) is H or alkyl whichis substituted or unsubstituted, or together with any of L², R^(a),R^(b), and R^(c) forms a ring that is substituted or unsubstituted, andR^(g) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or a pharmaceutically-acceptable salt,tautomer, or zwitterion thereof.

-   Embodiment A31. The method of embodiment A30, wherein aryl¹ is    substituted or unsubstituted phenyl, aryl² is substituted or    unsubstituted heteroaryl, and X is alkylene.-   Embodiment A32. The method of embodiment A31, wherein aryl¹ is    substituted phenyl, aryl² is substituted heteroaryl, and X is    methylene.-   Embodiment A33. The method of embodiment A32, wherein the compound    that activates Tie-2 is a compound of the formula:

wherein aryl¹ is para-substituted phenyl, aryl² is substitutedheteroaryl, X is methylene. L² is alkylene, alkenylene, or alkynylene,any of which is substituted or unsubstituted, or together with thenitrogen atom to which L is bound forms an amide linkage, a carbamatelinkage, a urethane linkage, or a sulfonamide linkage, or a chemicalbond. R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted. R^(b) is H, alkyl, alkenyl,alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,or heteroarylalkyl, any of which is substituted or unsubstituted. R^(c)is H or alkyl which is substituted or unsubstituted, and R^(d) is H oralkyl which is substituted or unsubstituted.

-   Embodiment A34. The method of embodiment A33, wherein aryl¹ is    para-substituted phenyl, aryl² is a substituted thiazole moiety. X    is methylene, L² together with the nitrogen atom to which L is bound    forms a carbamate linkage, IV is alkyl, which is substituted or    unsubstituted, R^(b)is arylalkyl, which is substituted or    unsubstituted, R^(c) is H, and R^(d) is H.-   Embodiment A35. The method of embodiment A34, wherein Aryl² is:

wherein R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a urethane group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, and R^(f) is H, OH, F, Cl, Br, I, CN,alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylicacid group, a carboxaldehyde group, an ester group, an amine group, anamide group, a carbonate group, a carbamate group, a urethane group, athioether group, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted.

-   Embodiment A36. The method of embodiment A35, wherein R^(e) is H,    OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl,    heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any    of which is substituted or unsubstituted, and R^(f) is H, OH, F, Cl,    Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is    substituted or unsubstituted.-   Embodiment A37. The method of embodiment A35, wherein R^(e) is H,    OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is    substituted or unsubstituted and R^(f) is alkyl, aryl, heterocyclyl,    or heteroaryl, any of which is substituted or unsubstituted.-   Embodiment A38. The method of embodiment A35, wherein aryl¹ is    4-phenylsulfamic acid, R^(a) is alkyl, which is substituted or    unsubstituted, R^(b) is arylalkyl, which is substituted or    unsubstituted, R^(e) is H; and R^(f) is heteroaryl.-   Embodiment A39. The method of embodiment A30, wherein the compound    is:

-   Embodiment A40. The method of embodiment A30, wherein the compound    is:

-   Embodiment A41. The method of embodiment A35, wherein aryl¹ is    4-phenylsulfamic acid, IV is alkyl, which is substituted or    unsubstituted, R^(b) is arylalkyl, which is substituted or    unsubstituted, R^(e) is H; and R^(f) is alkyl.-   Embodiment A42. The method of embodiment A30, wherein the compound    is:

-   Embodiment A43. The method of embodiment A32, wherein the compound    is:

-   Embodiment A44. The method of embodiment A34, wherein Aryl² is:

wherein R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a urethane group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, R^(f) is H, OH, F, Cl, Br, I, CN, alkyl,alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a urethane group, athioether group, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted.

-   Embodiment A45. The method of embodiment A44, wherein R^(e) is H,    OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl,    heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any    of which is substituted or unsubstituted and R^(f) is H, OH, F, Cl,    Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is    substituted or unsubstituted.-   Embodiment A46. The method of embodiment A44, wherein R^(e) is H,    OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is    substituted or unsubstituted and R^(f) is alkyl, aryl, heterocyclyl,    or heteroaryl, any of which is substituted or unsubstituted.-   Embodiment A47. The method of embodiment A44, wherein aryl¹ is    4-phenylsulfamic acid,

R^(a) is alkyl, which is substituted or unsubstituted, R^(b) isarylalkyl, which is substituted or unsubstituted, R^(e) is H; and R^(f)is heteroaryl.

-   Embodiment A48. The method of embodiment A30, wherein the compound    is:

-   Embodiment A49. The method of embodiment A30, wherein the compound    is:

-   Embodiment A50. The method of embodiment A40, wherein the agent that    improves the aqueous solubility of the compound that activates Tie-2    or the pharmaceutically-acceptable salt thereof comprises a    2-hydroxypropyl-β-cyclodextrin moiety.-   Embodiment A51. The method of embodiment A50, wherein the condition    is diabetic macular edema.-   Embodiment A52. The method of embodiment A51, wherein a plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is no greater than 500    ng/mL at about 0.25 hours after the administration.-   Embodiment A53. The method of embodiment A51, wherein a plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is about 50 ng/mL to    about 350 ng/mL at about 0.25 hours after the administration; about    30 ng/mL to about 350 ng/mL at about 1 hour after the    administration; about 10 ng/mL to about 200 ng/mL at about 2 hours    after the administration; and about 0 ng/mL to about 50 ng/mL at    about 4 hours after the administration.-   Embodiment A54. The method of embodiment A51, wherein a plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is for administration    of a dose of about 5 mg, about 50 ng/mL to about 100 ng/mL at about    0.25 hours after the administration; about 30 ng/mL to about 80    ng/mL at about 1 hour after the administration; about 10 ng/mL to    about 50 ng/mL at about 2 hours after the administration; and about    0 ng/mL to about 30 ng/mL at about 4 hours after the administration;    for administration of a dose of about 15 mg, about 120 ng/mL to    about 180 ng/mL at about 0.25 hours after the administration; about    70 ng/mL to about 130 ng/mL at about 1 hour after the    administration; about 20 ng/mL to about 70 ng/mL at about 2 hours    after the administration; and about 0 ng/mL to about 40 ng/mL at    about 4 hours after the administration; for administration of a dose    of about 22.5 mg, about 190 ng/mL to about 250 ng/mL at about 0.25    hours after the administration; about 170 ng/mL to about 240 ng/mL    at about 1 hour after the administration; about 70 ng/mL to about    120 ng/mL at about 2 hours after the administration; and about 10    ng/mL to about 60 ng/mL at about 4 hours after the administration;    and for administration of a dose of about 30 mg, about 250 ng/mL to    about 330 ng/mL at about 0.25 hours after the administration; about    270 ng/mL to about 330 ng/mL at about 1 hour after the    administration; about 130 ng/mL to about 180 ng/mL at about 2 hours    after the administration; and about 25 ng/mL to about 75 ng/mL at    about 4 hours after the administration.-   Embodiment B1. A method of treating a condition in a subject in need    thereof, the method comprising administering to the subject a    therapeutically-effective amount of a compound that activates Tie-2,    or a pharmaceutically-acceptable salt thereof, wherein the    administration provides a plasma concentration in the subject of the    compound that activates Tie-2 or the pharmaceutically-acceptable    salt thereof of about 25 ng/mL to about 500 ng/mL.-   Embodiment B2. The method of embodiment B1, wherein the plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is no greater than 350    ng/mL at about 0.25 hours after the administration.-   Embodiment B3. The method of embodiment B2, wherein the plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is greater than 50    ng/mL.-   Embodiment B4. The method of embodiment B1, wherein the plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is about 50 ng/mL to    about 350 ng/mL at about 0.25 hours after the administration; about    30 ng/mL to about 350 ng/mL at about 1 hour after the    administration; about 10 ng/mL to about 200 ng/mL at about 2 hours    after the administration; and about 0 ng/mL to about 50 ng/mL at    about 4 hours after the administration.-   Embodiment B5. The method of embodiment B1, wherein the plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is for administration    of a dose of about 5 mg, about 50 ng/mL to about 100 ng/mL at about    0.25 hours after the administration; about 30 ng/mL to about 80    ng/mL at about 1 hour after the administration; about 10 ng/mL to    about 50 ng/mL at about 2 hours after the administration; and about    0 ng/mL to about 30 ng/mL at about 4 hours after the administration;    for administration of a dose of about 15 mg, about 120 ng/mL to    about 180 ng/mL at about 0.25 hours after the administration; about    70 ng/mL to about 130 ng/mL at about 1 hour after the    administration; about 20 ng/mL to about 70 ng/mL at about 2 hours    after the administration; and about 0 ng/mL to about 40 ng/mL at    about 4 hours after the administration; for administration of a dose    of about 22.5 mg, about 190 ng/mL to about 250 ng/mL at about 0.25    hours after the administration; about 170 ng/mL to about 240 ng/mL    at about 1 hour after the administration; about 70 ng/mL to about    120 ng/mL at about 2 hours after the administration; and about 10    ng/mL to about 60 ng/mL at about 4 hours after the administration;    and for administration of a dose of about 30 mg, about 250 ng/mL to    about 330 ng/mL at about 0.25 hours after the administration; about    270 ng/mL to about 330 ng/mL at about 1 hour after the    administration; about 130 ng/mL to about 180 ng/mL at about 2 hours    after the administration; and about 25 ng/mL to about 75 ng/mL at    about 4 hours after the administration.-   Embodiment B6. The method of embodiment B1, wherein the compound    that activates Tie-2, or the pharmaceutically-acceptable salt    thereof, is administered in a unit dosage form, wherein the unit    dosage form further comprises a pharmaceutically-acceptable    excipient.-   Embodiment B7. The method of embodiment B6, wherein the    pharmaceutically-acceptable excipient comprises a poly-ethylene    glycol moiety.-   Embodiment B8. The method of embodiment B6, wherein the    pharmaceutically-acceptable excipient comprises a cyclodextrin    moiety.-   Embodiment B9. The method of embodiment B6, wherein the    pharmaceutically-acceptable excipient comprises a    2-hydroxypropyl-β-cyclodextrin moiety.-   Embodiment B10. The method of embodiment B6, wherein the    pharmaceutically-acceptable excipient comprises a    sulfobutylether-β-cyclodextrin moiety.-   Embodiment B11. The method of embodiment B6, wherein the compound    that activates Tie-2, or the pharmaceutically-acceptable salt    thereof, and the pharmaceutically-acceptable excipient are held in a    complex by non-covalent interactions.-   Embodiment B12. The method of embodiment B6, wherein the    pharmaceutically-acceptable excipient comprises a surfactant moiety.-   Embodiment B13. The method of embodiment B 1, wherein the    therapeutically-effective amount is from about 0.1 mg to about 100    mg.-   Embodiment B14. The method of embodiment B 1, wherein the    therapeutically-effective amount is from about 0.5 mg to about 30    mg.-   Embodiment B15. The method of embodiment B 1, wherein the    administration is subcutaneous.-   Embodiment B16. The method of embodiment B 1, wherein the    administration is to an eye. Embodiment B17. The method of    embodiment B1, wherein the condition is an ocular condition.-   Embodiment B18. The method of embodiment B 1, wherein the condition    is diabetic macular edema.-   Embodiment B19. The method of embodiment B 1, wherein the condition    is diabetic retinopathy.-   Embodiment B20. The method of embodiment B1, wherein the condition    is macular degeneration.-   Embodiment B21. The method of embodiment B1, wherein the condition    is vascular leak.-   Embodiment B22. The method of embodiment B1, wherein the condition    is a cancer.-   Embodiment B23. The method of embodiment B1, wherein the subject is    a human.-   Embodiment B24. The method of embodiment B1, wherein the compound    that activates Tie-2 or the pharmaceutically-acceptable salt thereof    binds HPTP-beta.-   Embodiment B25. The method of embodiment B1, wherein the compound    that activates Tie-2 or the pharmaceutically-acceptable salt thereof    inhibits HPTP-beta.-   Embodiment B26. The method of embodiment B1, wherein the compound    that activates Tie-2 or the pharmaceutically-acceptable salt thereof    is a phosphate mimetic.-   Embodiment B27. The method of embodiment B1, wherein the compound    that activates Tie-2 comprises an amino acid backbone.-   Embodiment B28. The method of embodiment B1, wherein the compound    that activates Tie-2 comprises a sulfamic acid.-   Embodiment B29. The method of embodiment B1, wherein the subject's    visual acuity improves by at least 5 letters.-   Embodiment B30. The method of embodiment B9, wherein the compound    that activates Tie-2 is:

or a pharmaceutically-acceptable salt or zwitterion thereof.

-   Embodiment B31. The method of embodiment B30, wherein a plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is no greater than 350    ng/mL at about 0.25 hours after the administration.-   Embodiment B32. The method of embodiment B30, wherein the plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is about 50 ng/mL to    about 350 ng/mL at about 0.25 hours after the administration; about    30 ng/mL to about 350 ng/mL at about 1 hour after the    administration; about 10 ng/mL to about 200 ng/mL at about 2 hours    after the administration; and about 0 ng/mL to about 50 ng/mL at    about 4 hours after the administration.-   Embodiment B33. The method of embodiment B30, wherein the plasma    concentration in the subject of the compound that activates Tie-2 or    the pharmaceutically-acceptable salt thereof is for administration    of a dose of about 5 mg, about 50 ng/mL to about 100 ng/mL at about    0.25 hours after the administration; about 30 ng/mL to about 80    ng/mL at about 1 hour after the administration; about 10 ng/mL to    about 50 ng/mL at about 2 hours after the administration; and about    0 ng/mL to about 30 ng/mL at about 4 hours after the administration;    for administration of a dose of about 15 mg, about 120 ng/mL to    about 180 ng/mL at about 0.25 hours after the administration; about    70 ng/mL to about 130 ng/mL at about 1 hour after the    administration; about 20 ng/mL to about 70 ng/mL at about 2 hours    after the administration; and about 0 ng/mL to about 40 ng/mL at    about 4 hours after the administration; for administration of a dose    of about 22.5 mg, about 190 ng/mL to about 250 ng/mL at about 0.25    hours after the administration; about 170 ng/mL to about 240 ng/mL    at about 1 hour after the administration; about 70 ng/mL to about    120 ng/mL at about 2 hours after the administration; and about 10    ng/mL to about 60 ng/mL at about 4 hours after the administration;    and for administration of a dose of about 30 mg, about 250 ng/mL to    about 330 ng/mL at about 0.25 hours after the administration; about    270 ng/mL to about 330 ng/mL at about 1 hour after the    administration; about 130 ng/mL to about 180 ng/mL at about 2 hours    after the administration; and about 25 ng/mL to about 75 ng/mL at    about 4 hours after the administration.-   Embodiment B34. The method of any above embodiment wherein the    compound that activates Tie-2 is any compound described herein.-   Embodiment C1. A pharmaceutical composition comprising a compound    that activates Tie-2, or a pharmaceutically-acceptable salt thereof    and an agent that increases solubility of the compound that    activates Tie-2, or the pharmaceutically-acceptable salt thereof    compared to solubility in absence of the agent.-   Embodiment C2. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    comprises a polymer.-   Embodiment C3. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    comprises a poly-ethylene glycol moiety.-   Embodiment C4. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    comprises a cyclodextrin moiety.-   Embodiment C5. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    comprises a 2-hydroxypropyl-β-cyclodextrin moiety.-   Embodiment C6. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    comprises a sulfobutylether-β-cyclodextrin moiety.-   Embodiment C7. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    comprises a surfactant moiety.-   Embodiment C8. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    increases acqueous solubility by at least 10% at each of 5° C.,    ambient temperature, and 50° C.-   Embodiment C9. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    improves solubility by at least 25%.-   Embodiment C10. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof    improves solubility by at least 50%.-   Embodiment C11. The pharmaceutical composition of embodiment C1,    wherein the agent that increases solubility of the compound that    activates Tie-2 or the pharmaceutically-acceptable salt thereof is a    cyclodextrin, and the pharmaceutical composition has a solubility of    the compound that activates Tie-2, or the    pharmaceutically-acceptable salt thereof, that is greater than that    of an alternative formulation, wherein the alternative formulation    comprises the compound that activates Tie-2, or the    pharmaceutically-acceptable salt thereof; the cyclodexrin; and a    polyethylene glycol moiety.-   Embodiment C12. The pharmaceutical composition of embodiment C1,    wherein the compound that activates Tie-2, or the    pharmaceutically-acceptable salt thereof, is present in an amount    from about 0.1 mg to about 100 mg.-   Embodiment C13. The pharmaceutical composition of embodiment C1,    wherein the compound that activates Tie-2, or the    pharmaceutically-acceptable salt thereof, is present in an amount    from about 0.5 mg to about 30 mg.-   Embodiment C14. The pharmaceutical composition of embodiment C1,    wherein the pharmaceutical composition is stable at about 5° C. for    at least 30 days.-   Embodiment C15. The pharmaceutical composition of embodiment C1,    wherein the pharmaceutical composition is stable at about 50° C. for    at least 30 days.-   Embodiment C16. The pharmaceutical composition of embodiment C1,    wherein the compound that activates Tie-2, or the    pharmaceutically-acceptable salt thereof, and the agent that    increases solubility of the compound that activates Tie-2 or the    pharmaceutically-acceptable salt thereof are in a unit dosage form.-   Embodiment C17. The pharmaceutical composition of embodiment C16,    wherein the unit dosage for further comprises a    pharmaceutically-acceptable carrier.-   Embodiment C18. The pharmaceutical composition of embodiment C16,    wherein the unit dosage form is formulated for subcutaneous    administration.-   Embodiment C19. The pharmaceutical composition of embodiment C16,    wherein the unit dosage form is formulated for administration to an    eye.-   Embodiment C20. The pharmaceutical composition of embodiment C1,    wherein the compound that activates Tie-2 or the    pharmaceutically-acceptable salt thereof binds HPTP-beta.-   Embodiment C21. The pharmaceutical composition of embodiment C1,    wherein the compound that activates Tie-2 or the    pharmaceutically-acceptable salt thereof inhibits HPTP-beta.-   Embodiment C22. The pharmaceutical composition of embodiment C1,    wherein the compound that activates Tie-2 or the    pharmaceutically-acceptable salt thereof is a phosphate mimetic.-   Embodiment C23. The pharmaceutical composition of embodiment C1,    wherein the compound that activates Tie-2 comprises an amino acid    backbone.-   Embodiment C24. The pharmaceutical composition of embodiment C1,    wherein the compound that activates Tie-2 comprises a sulfamic acid.-   Embodiment C25. The pharmaceutical composition of any above    embodiment wherein the compound that activates Tie-2 is any compound    described herein.-   Embodiment D1. A pharmaceutical composition comprising a Tie-2    activator or a pharmaceutically-acceptable salt thereof, and an    antibody.-   Embodiment D2. The pharmaceutical composition of embodiment D1,    wherein the Tie-2 activator or the pharmaceutically-acceptable salt    thereof binds HPTP-beta.-   Embodiment D3. The pharmaceutical composition of embodiment D1,    wherein the Tie-2 activator or the pharmaceutically-acceptable salt    thereof inhibits HPTP-beta.-   Embodiment D4. The pharmaceutical composition of embodiment D1,    wherein the Tie-2 activator or the pharmaceutically-acceptable salt    thereof is a phosphate mimetic.-   Embodiment D5. The pharmaceutical composition of embodiment D1,    wherein the Tie-2 activator comprises an amino acid backbone.-   Embodiment D6. The pharmaceutical composition of embodiment D1,    wherein the Tie-2 activator comprises a sulfamic acid.-   Embodiment D7. The pharmaceutical composition of embodiment D1,    wherein the antibody binds HPTP-beta.-   Embodiment D8. The pharmaceutical composition of embodiment D1,    wherein the antibody is an anti-VEGF agent.-   Embodiment D9. The pharmaceutical composition of embodiment D1,    wherein the antibody is ranibizumab.-   Embodiment D10. The pharmaceutical composition of embodiment D1,    wherein the antibody is bevacizumab.-   Embodiment D11. The pharmaceutical composition of embodiment D1,    wherein the antibody is aflibercept.-   Embodiment D12. The pharmaceutical composition of embodiment D1,    wherein the antibody comprises SEQ ID NO: 1.-   Embodiment D13. The pharmaceutical composition of embodiment D1,    wherein the antibody comprises SEQ ID NO: 2.-   Embodiment D14. The pharmaceutical composition of embodiment D1,    wherein the antibody comprises SEQ ID NO: 1 and SEQ ID NO: 2.-   Embodiment D15. The pharmaceutical composition of embodiment D1,    wherein the Tie-2 activator or the pharmaceutically-acceptable salt    thereof and the antibody are in a unit dosage form, wherein the unit    dosage form further comprises a pharmaceutically-acceptable    excipient.-   Embodiment D16. The pharmaceutical composition of embodiment D15,    wherein the pharmaceutically-acceptable excipient comprises a    poly-ethylene glycol moiety.-   Embodiment D17. The pharmaceutical composition of embodiment D15,    wherein the pharmaceutically-acceptable excipient comprises a    cyclodextrin moiety.-   Embodiment D18. The pharmaceutical composition of embodiment D15,    wherein the pharmaceutically-acceptable excipient comprises a    2-hydroxypropyl-β-cyclodextrin moiety.-   Embodiment D19. The pharmaceutical composition of embodiment D15,    wherein the pharmaceutically-acceptable excipient comprises a    sulfobutylether-β-cyclodextrin moiety.-   Embodiment D20. The pharmaceutical composition of embodiment D15,    wherein the Tie-2 activator, or the pharmaceutically-acceptable salt    thereof, and the pharmaceutically-acceptable excipient are held in a    complex by non-covalent interactions.-   Embodiment D21. The pharmaceutical composition of embodiment D15,    wherein the pharmaceutically-acceptable excipient comprises a    surfactant moiety.-   Embodiment D22. The pharmaceutical composition of embodiment D15,    wherein the unit dosage form is formulated for subcutaneous    administration.-   Embodiment D23. The pharmaceutical composition of embodiment D15,    wherein the unit dosage form is formulated for administration to an    eye.-   Embodiment D24. The pharmaceutical composition of embodiment D1,    wherein the Tie-2 activator is present in an amount from about 0.1    mg to about 100 mg.-   Embodiment D25. The pharmaceutical composition of embodiment D1,    wherein the Tie-2 activator is present in an amount from about 0.5    mg to about 30 mg.-   Embodiment D26. The pharmaceutical composition of embodiment D1,    wherein the antibody is present in an amount from about 0.01 mg to    about 5 mg.-   Embodiment D27. The pharmaceutical composition of embodiment D1,    wherein the antibody is present in an amount from about 0.1 mg to    about 5 mg.-   Embodiment D28. The pharmaceutical composition of any above    embodiment wherein the compound that activates Tie-2 is any compound    described herein.-   Embodiment D1. A kit comprising a Tie-2 activator or a    pharmaceutically-acceptable salt thereof, an antibody, and written    instructions on use of the kit in treatment of a condition.-   Embodiment D2. The kit of embodiment D1, wherein the condition is an    ocular condition.-   Embodiment D3. The kit of embodiment D1, wherein the condition is an    ocular condition.-   Embodiment D4. The kit of embodiment D1, wherein the condition is    diabetic macular edema.-   Embodiment D5. The kit of embodiment D1, wherein the condition is    diabetic retinopathy.-   Embodiment D6. The kit of embodiment D1, wherein the condition is    macular degeneration.-   Embodiment D7. The kit of embodiment D1, wherein the condition is    vascular leak.-   Embodiment D8. The kit of embodiment D1, wherein the condition is a    cancer.-   Embodiment D9. The kit of embodiment D1, wherein the instructions    describe administration by subcutaneous injection.-   Embodiment D10. The kit of embodiment D1, wherein the instructions    describe administration to an eye.-   Embodiment D11. The kit of any above embodiment wherein the Tie-2    activator is any compound described herein.-   Embodiment E1. A method of treating a condition, the method    comprising administering to a subject in need thereof a    therapeutically-effective amount of a Tie-2 activator or a    pharmaceutically-acceptable salt thereof and a    therapeutically-effective amount of an antibody.-   Embodiment E2. The method of embodiment E1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof binds    HPTP-beta.-   Embodiment E3. The method of embodiment E1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof inhibits    HPTP-beta.-   Embodiment E4. The method of embodiment E1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof is a    phosphate mimetic.-   Embodiment E5. The method of embodiment E1, wherein the Tie-2    activator comprises an amino acid backbone.-   Embodiment E6. The method of embodiment E1, wherein the Tie-2    activator comprises a sulfamic acid.-   Embodiment E7. The method of embodiment E1, wherein the antibody    binds HPTP-beta.-   Embodiment E8. The method of embodiment E1, wherein the antibody is    an anti-VEGF agent.-   Embodiment E9. The method of embodiment E1, wherein the antibody is    ranibizumab.-   Embodiment E10. The method of embodiment E1, wherein the antibody is    bevacizumab.-   Embodiment E11. The method of embodiment E1, wherein the antibody is    aflibercept.-   Embodiment E12. The method of embodiment E1, wherein the antibody    comprises SEQ ID NO: 1.-   Embodiment E13. The method of embodiment E1, wherein the antibody    comprises SEQ ID NO: 2.-   Embodiment E14. The method of embodiment E1, wherein the antibody    comprises SEQ ID NO: 1 and SEQ ID NO: 2.-   Embodiment E15. The method of embodiment E1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof and the    antibody are in a unit dosage form, wherein the unit dosage form    further comprises a pharmaceutically-acceptable excipient.-   Embodiment E16. The method of embodiment E15, wherein the    pharmaceutically-acceptable excipient comprises a poly-ethylene    glycol moiety.-   Embodiment E17. The method of embodiment E15, wherein the    pharmaceutically-acceptable excipient comprises a cyclodextrin    moiety.-   Embodiment E18. The method of embodiment E15, wherein the    pharmaceutically-acceptable excipient comprises a    2-hydroxypropyl-β-cyclodextrin moiety.-   Embodiment E19. The method of embodiment E15, wherein the    pharmaceutically-acceptable excipient comprises a    sulfobutylether-β-cyclodextrin moiety.-   Embodiment E20. The method of embodiment E15, wherein the Tie-2    activator, or the pharmaceutically-acceptable salt thereof, and the    pharmaceutically-acceptable excipient are held in a complex by    non-covalent interactions.-   Embodiment E21. The method of embodiment E15, wherein the    pharmaceutically-acceptable excipient comprises a surfactant moiety.-   Embodiment E22. The method of embodiment E1, wherein the    therapeutically-effective amount of the Tie-2 activator or the    pharmaceutically-acceptable salt thereof is from about 0.1 mg to    about 100 mg.-   Embodiment E23. The method of embodiment E1, wherein the    therapeutically-effective amount of the Tie-2 activator or the    pharmaceutically-acceptable salt thereof is from about 0.5 mg to    about 30 mg.-   Embodiment E24. The method of embodiment E1, wherein the    therapeutically-effective amount of the antibody is from about 0.01    mg to about 5 mg.-   Embodiment E25. The method of embodiment E1, wherein the    therapeutically-effective amount of the antibody is from about 0.1    mg to about 5 mg.-   Embodiment E26. The method of embodiment E1, wherein the    administration of the Tie-2 activator or the    pharmaceutically-acceptable salt thereof is subcutaneous    administration.-   Embodiment E27. The method of embodiment E1, wherein the    administration of the antibody is subcutaneous administration.-   Embodiment E28. The method of embodiment E1, wherein the    administration of the Tie-2 activator or the    pharmaceutically-acceptable salt thereof is to an eye.-   Embodiment E29. The method of embodiment E1, wherein the    administration of the antibody is to an eye.-   Embodiment E30. The method of embodiment E1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof and the    antibody are administered simultaneously.-   Embodiment E31. The method of embodiment E1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof and the    antibody are administered sequentially.-   Embodiment E32. The method of embodiment E31, wherein the sequential    administration is administration of the Tie-2 activator or the    pharmaceutically-acceptable salt thereof and the antibody on the    same day.-   Embodiment E33. The method of embodiment E31, wherein the sequential    administration is administration of the Tie-2 activator or the    pharmaceutically-acceptable salt thereof and the antibody within one    month.-   Embodiment E34. The method of embodiment E1, wherein the condition    is an ocular condition.-   Embodiment E35. The method of embodiment E1, wherein the condition    is diabetic macular edema.-   Embodiment E36. The method of embodiment E1, wherein the condition    is diabetic retinopathy.-   Embodiment E37. The method of embodiment E1, wherein the condition    is macular degeneration.-   Embodiment E38. The method of embodiment E1, wherein the condition    is vascular leak.-   Embodiment E39. The method of embodiment E1, wherein the condition    is a cancer.-   Embodiment E40. The method of embodiment E1, wherein the subject is    a human-   Embodiment E41. The method of embodiment E1, wherein the subject's    visual acuity improves by at least 5 letters.-   Embodiment E42. The method of any above embodiment wherein the Tie-2    activator is any compound described herein.-   Embodiment F1. A complex comprising a Tie-2 activator, or a    pharmaceutically-acceptable salt thereof, and a molecule comprising    a channel, wherein the compound that activates Tie-2, or the    pharmaceutically-acceptable salt thereof is held in the channel of    the molecule by non-covalent interactions.-   Embodiment F2. The complex of embodiment F1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof binds    HPTP-beta.-   Embodiment F3. The complex of embodiment F1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof inhibits    HPTP-beta.-   Embodiment F4. The complex of embodiment F1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof is a    phosphate mimetic.-   Embodiment F5. The complex of embodiment F1, wherein the Tie-2    activator comprises an amino acid backbone.-   Embodiment F6. The complex of embodiment F1, wherein the Tie-2    activator comprises a sulfamic acid.-   Embodiment F7. The complex of embodiment F1, wherein the molecule    comprising the channel comprises a cyclodextrin moiety.-   Embodiment F8. The complex of embodiment F1, wherein the molecule    comprising the channel comprises a 2-hydroxypropyl-β-cyclodextrin    moiety.-   Embodiment F9. The complex of embodiment F1, wherein the molecule    comprising the channel comprises a sulfobutylether-β-cyclodextrin    moiety.-   Embodiment F10. The complex of embodiment F1, wherein the complex is    more soluble in water than is the Tie-2 activator in the absence of    the molecule comprising the channel-   Embodiment F11. The complex of any above embodiment wherein the    Tie-2 activator is any compound described herein.-   Embodiment G1. A method of treating a condition, the method    comprising administering to a subject in need thereof a    therapeutically-effective amount of complex comprising a Tie-2    activator, or a pharmaceutically-acceptable salt thereof and a    molecule comprising a channel, wherein the Tie-2 activator or the    pharmaceutically-acceptable salt thereof is held in the channel of    the molecule by non-covalent interactions.-   Embodiment G2. The method of embodiment G1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof binds    HPTP-beta.-   Embodiment G3. The method of embodiment G1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof inhibits    HPTP-beta.-   Embodiment G4. The method of embodiment G1, wherein the Tie-2    activator or the pharmaceutically-acceptable salt thereof is a    phosphate mimetic.-   Embodiment G5. The method of embodiment G1, wherein the Tie-2    activator comprises an amino acid backbone.-   Embodiment G6. The method of embodiment G1, wherein the Tie-2    activator comprises a sulfamic acid.-   Embodiment G7. The method of embodiment G1, wherein the molecule    comprising the channel comprises a cyclodextrin moiety.-   Embodiment G8. The method of embodiment G1, wherein the molecule    comprising the channel comprises a 2-hydroxypropyl-β-cyclodextrin    moiety.-   Embodiment G9. The method of embodiment G1, wherein the molecule    comprising the channel comprises a sulfobutylether-β-cyclodextrin    moiety.-   Embodiment G10. The method of embodiment G1, wherein the complex is    more soluble in water than is the Tie-2 activator in the absence of    the molecule comprising the channel.-   Embodiment G11. The method of embodiment G1, wherein the    administration of the complex is subcutaneous administration.-   Embodiment G12. The method of embodiment G1, wherein the    administration of the complex is to an eye.-   Embodiment G13. The method of embodiment G1, wherein the complex is    in a unit dosage form.-   Embodiment G14. The method of embodiment G1, wherein the    therapeutically-effective amount of the complex is from about 0.1 mg    to about 300 mg.-   Embodiment G15. The method of embodiment G1, wherein the    therapeutically-effective amount of the Tie-2 activator or the    pharmaceutically-acceptable salt thereof is from about 0.5 mg to    about 100 mg.-   Embodiment G16. The method of embodiment G1, wherein the condition    is an ocular condition.-   Embodiment G17. The method of embodiment G1, wherein the condition    is diabetic macular edema.-   Embodiment G18. The method of embodiment G1, wherein the condition    is diabetic retinopathy.-   Embodiment G19. The method of embodiment G1, wherein the condition    is macular degeneration.-   Embodiment G20. The method of embodiment G1, wherein the condition    is vascular leak.-   Embodiment G21. The method of embodiment G1, wherein the condition    is a cancer.-   Embodiment G22. The method of embodiment G1, further comprising    administering to the subject a therapeutically-effective amount of    an additional therapeutic agent.

Embodiment G23. The method of embodiment G22, wherein the additionaltherapeutic agent is an antibody.

-   Embodiment G24. The method of embodiment G22, wherein the additional    therapeutic agent binds HPTP-beta.-   Embodiment G25. The method of embodiment G22, wherein the additional    therapeutic agent is an anti-VEGF agent.-   Embodiment G26. The method of embodiment G22, wherein the additional    therapeutic agent is ranibizumab.-   Embodiment G27. The method of embodiment G22, wherein the additional    therapeutic agent is bevacizumab.-   Embodiment G28. The method of embodiment G22, wherein the additional    therapeutic agent is aflibercept.-   Embodiment G29. The method of embodiment G22, wherein the additional    therapeutic agent comprises SEQ ID NO: 1.-   Embodiment G30. The method of embodiment G22, wherein the additional    therapeutic agent comprises SEQ ID NO: 2.-   Embodiment G31. The method of embodiment G22, wherein the additional    therapeutic agent comprises SEQ ID NO: 1 and SEQ ID NO: 2.-   Embodiment G32. The method of embodiment G22, wherein the    therapeutically-effective amount of the additional therapeutic agent    is from about 0.01 mg to about 5 mg.-   Embodiment G33. The method of embodiment G22, wherein the    therapeutically-effective amount of the additional therapeutic agent    is from about 0.1 mg to about 5 mg.-   Embodiment G34. The method of embodiment G22, wherein the    administration of the additional therapeutic agent is subcutaneous    administration.-   Embodiment G35. The method of embodiment G22, wherein the    administration of the additional therapeutic agent is to an eye.-   Embodiment G36. The method of embodiment G22, wherein the complex    and the additional therapeutic agent are administered    simultaneously.-   Embodiment G37. The method of embodiment G22, wherein the complex    and the additional therapeutic agent are administered sequentially.-   Embodiment G38. The method of embodiment G37, wherein the sequential    administration is administration of the Tie-2 activator or the    pharmaceutically-acceptable salt thereof and the antibody on the    same day.-   Embodiment G39. The method of embodiment G37, wherein the sequential    administration is administration of the Tie-2 activator or the    pharmaceutically-acceptable salt thereof and the antibody within one    month.-   Embodiment G40. The method of embodiment G1, wherein the subject is    a human.-   Embodiment G41. The method of embodiment G1, wherein the subject's    visual acuity improves by at least 5 letters.-   Embodiment G42. The method of any above embodiment wherein the Tie-2    activator is any compound described herein.

1-54. (canceled)
 55. A method for treating a condition in a subject inneed thereof, comprising: administering to the subject atherapeutically-effective amount of a Tie-2 activator; and administeringto the subject a therapeutically-effective amount of an anti-VEGF agent,wherein the Tie-2 activator is a compound of the formula:

wherein: Aryl¹ is an aryl group which is substituted or unsubstituted;Aryl² is an aryl group which is substituted or unsubstituted; X isalkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, anamide linkage, an ester linkage, a thioether linkage, a carbamatelinkage, a carbonate linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; and Y is H, aryl,heteroaryl, NH(aryl), NH(heteroaryl), NHSO2R^(g), or NHCOR^(g), any ofwhich is substituted or unsubstituted, or

wherein: L² is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L² is bound forms an amide linkage, a carbamate linkage, or asulfonamide linkage, or a chemical bond, or together with any of R^(a),R^(b), R^(c), and R^(d) forms a ring that is substituted orunsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L²,R^(b), R^(c), and R^(d) forms a ring that is substituted orunsubstituted; R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L²,R^(a), R^(c), and R^(d) forms a ring that is substituted orunsubstituted; R^(c) is H or alkyl which is substituted orunsubstituted, or together with any of L², R^(a), R^(b), and R^(d) formsa ring that is substituted or unsubstituted; R^(d) is H or alkyl whichis substituted or unsubstituted, or together with any of L², R^(a),R^(b), and R^(c) forms a ring that is substituted or unsubstituted; andR^(g) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or a pharmaceutically-acceptable salt orzwitterion thereof
 56. The method of claim 55, wherein the Tie-2activator inhibits HPTP-β.
 57. The method of claim 55, wherein thecondition is diabetic macular edema.
 58. The method of claim 55, whereinthe condition is wet age-related macular degeneration.
 59. The method ofclaim 55, wherein the condition is diabetic retinopathy.
 60. The methodof claim 55, wherein the condition is retinal vein occlusion.
 61. Themethod of claim 55, wherein the administering is by intravitrealinjection.
 62. The method of claim 55, wherein the administering is bysubconjunctival injection.
 63. The method of claim 55, wherein theadministering is by a solid implant.
 64. The method of claim 55, whereinthe therapeutically-effective amount of the Tie-2 activator is fromabout 0.1 mg to about 100 mg.
 65. The method of claim 55, wherein theTie-2 activator is:

or a pharmaceutically-acceptable salt or zwitterion thereof
 66. Themethod of claim 55, wherein the Tie-2 activator is:

or a pharmaceutically-acceptable salt or zwitterion thereof
 67. Themethod of claim 55, wherein the anti-VEGF agent is ranibizumab.
 68. Themethod of claim 55, wherein the anti-VEGF agent is bevacizumab.
 69. Themethod of claim 55, wherein the anti-VEGF agent is aflibercept.
 70. Themethod of claim 75, wherein the anti-VEGF agent is dexamethasone. 71.The method of claim 75, wherein the anti-VEGF agent is fluocinolone. 72.The method of claim 55, wherein the subject is human.
 73. The method ofclaim 77, wherein the Tie-2 activator and the anti-VEGF agent areadministered simultaneously.
 74. The method of claim 77, wherein theTie-2 activator and the anti-VEGF agent are administered sequentially.